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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>ML368 Identification of Imidazopyridines as Selective Inhibitors of the Cytochrome P450 Enzyme CYP3A4 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="ML368 Identification of Imidazopyridines as Selective Inhibitors of the Cytochrome P450 Enzyme CYP3A4">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2014/09/18">
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<meta name="citation_author" content="Michael Cameron">
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<meta name="citation_author" content="Ted Kamenecka">
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<meta name="citation_author" content="Franck Madoux">
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<meta name="citation_author" content="Peter Chase">
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<meta name="citation_author" content="William Roush">
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<meta name="citation_author" content="Peter Hodder">
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<meta name="citation_author" content="Patrick R. Griffin">
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<meta name="citation_pmid" content="24479199">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK179830/">
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<meta name="DC.Title" content="ML368 Identification of Imidazopyridines as Selective Inhibitors of the Cytochrome P450 Enzyme CYP3A4">
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<meta name="DC.Contributor" content="Michael Cameron">
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<meta name="DC.Contributor" content="Ted Kamenecka">
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<meta name="DC.Contributor" content="Franck Madoux">
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<meta name="DC.Contributor" content="Peter Chase">
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<meta name="DC.Contributor" content="William Roush">
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<meta name="DC.Contributor" content="Peter Hodder">
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<meta name="DC.Contributor" content="Patrick R. Griffin">
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<meta name="DC.Date" content="2014/09/18">
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<meta name="description" content="Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity. During our medicinal chemistry and biology effort pursued under our existing LRH1 inverse agonist Extended Characterization (EC) project, we identified several compounds belonging to the imidazopyridine scaffold with activity against the cytochrome enzymes. As a result we have explored how these compounds act on the CYP enzymes described within our approved EC proposal. Associated toxicities due to CYP3A4 related drug–drug interactions have led to clinical failure and withdrawal from market of previously approved pharmaceuticals. Mibefradil (Posicor), a potent inhibitor of CYP3A4, was withdrawn from the market after numerous reports of serious drug–drug interactions. Terfenadine (Seldane) and Cisapride (Propulsid) were withdrawn after patients taking the recommended dose along with CYP3A4 inhibitors such as ketoconazole developed heart arrhythmia leading to heart attack or death. To date, no substrates have been identified that are metabolized exclusively by only one of the enzymes. However, using recombinantly expressed enzymes, several substrates have been shown to have higher catalytic efficiency for either CYP3A4 or CYP3A5. Similarly, no highly selective inhibitors have been identified, but many do show two to fivefold preference for one of the two enzymes. Many of these have been associated with time-dependent inactivation where CYP3A4 appears to be more susceptible to time-dependent inactivation than does CYP3A5. The probe identified herein was tested by the assay provider's lab and the Scripps team using microsomal-based and biochemical assays. These probes will provide useful tools to elucidate the roles of this enzyme in cell metabolism, and will enable studies to differentiate the actions of the diverse members of the CYP family of enzymes.">
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<meta name="og:description" content="Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity. During our medicinal chemistry and biology effort pursued under our existing LRH1 inverse agonist Extended Characterization (EC) project, we identified several compounds belonging to the imidazopyridine scaffold with activity against the cytochrome enzymes. As a result we have explored how these compounds act on the CYP enzymes described within our approved EC proposal. Associated toxicities due to CYP3A4 related drug–drug interactions have led to clinical failure and withdrawal from market of previously approved pharmaceuticals. Mibefradil (Posicor), a potent inhibitor of CYP3A4, was withdrawn from the market after numerous reports of serious drug–drug interactions. Terfenadine (Seldane) and Cisapride (Propulsid) were withdrawn after patients taking the recommended dose along with CYP3A4 inhibitors such as ketoconazole developed heart arrhythmia leading to heart attack or death. To date, no substrates have been identified that are metabolized exclusively by only one of the enzymes. However, using recombinantly expressed enzymes, several substrates have been shown to have higher catalytic efficiency for either CYP3A4 or CYP3A5. Similarly, no highly selective inhibitors have been identified, but many do show two to fivefold preference for one of the two enzymes. Many of these have been associated with time-dependent inactivation where CYP3A4 appears to be more susceptible to time-dependent inactivation than does CYP3A5. The probe identified herein was tested by the assay provider's lab and the Scripps team using microsomal-based and biochemical assays. These probes will provide useful tools to elucidate the roles of this enzyme in cell metabolism, and will enable studies to differentiate the actions of the diverse members of the CYP family of enzymes.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK179830_"><span class="title" itemprop="name">ML368 Identification of Imidazopyridines as Selective Inhibitors of the Cytochrome P450 Enzyme CYP3A4</span></h1><p class="contribs">Cameron M, Kamenecka T, Madoux F, et al.</p><p class="fm-aai"><a href="#_NBK179830_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity. During our medicinal chemistry and biology effort pursued under our existing LRH1 inverse agonist Extended Characterization (EC) project, we identified several compounds belonging to the imidazopyridine scaffold with activity against the cytochrome enzymes. As a result we have explored how these compounds act on the CYP enzymes described within our approved EC proposal. Associated toxicities due to CYP3A4 related drug–drug interactions have led to clinical failure and withdrawal from market of previously approved pharmaceuticals. Mibefradil (Posicor), a potent inhibitor of CYP3A4, was withdrawn from the market after numerous reports of serious drug–drug interactions. Terfenadine (Seldane) and Cisapride (Propulsid) were withdrawn after patients taking the recommended dose along with CYP3A4 inhibitors such as ketoconazole developed heart arrhythmia leading to heart attack or death. To date, no substrates have been identified that are metabolized exclusively by only one of the enzymes. However, using recombinantly expressed enzymes, several substrates have been shown to have higher catalytic efficiency for either CYP3A4 or CYP3A5. Similarly, no highly selective inhibitors have been identified, but many do show two to fivefold preference for one of the two enzymes. Many of these have been associated with time-dependent inactivation where CYP3A4 appears to be more susceptible to time-dependent inactivation than does CYP3A5. The probe identified herein was tested by the assay provider's lab and the Scripps team using microsomal-based and biochemical assays. These probes will provide useful tools to elucidate the roles of this enzyme in cell metabolism, and will enable studies to differentiate the actions of the diverse members of the CYP family of enzymes.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> U54 <a href="/nuccore/1608696581" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">MH084512</a></p><p><b>Screening Center Name & PI:</b> The Scripps Research Institute Molecular Screening Center (SRIMSC), Hugh Rosen</p><p><b>Chemistry Center Name & PI:</b> The Scripps Research Institute Molecular Screening Center (SRIMSC), Hugh Rosen</p><p><b>Assay Submitter & Institution:</b> Patrick R. Griffin, Scripps Florida</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602418" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602418</a></p><div id="ml368.s1"><h2 id="_ml368_s1_">Probe Structure & Characteristics</h2><div id="ml368.f1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml368f1&p=BOOKS&id=179830_ml368f1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK179830/bin/ml368f1.jpg" alt="Image ml368f1" class="tileshop" title="Click on image to zoom" /></a></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml368t1"><a href="/books/NBK179830/table/ml368.t1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml368t1" rid-ob="figobml368t1"><img class="small-thumb" src="/books/NBK179830/table/ml368.t1/?report=thumb" src-large="/books/NBK179830/table/ml368.t1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml368.t1"><a href="/books/NBK179830/table/ml368.t1/?report=objectonly" target="object" rid-ob="figobml368t1">Table</a></h4></div></div></div><div id="ml368.s2"><h2 id="_ml368_s2_">Recommendations for scientific use of the probe</h2><ul><li class="half_rhythm"><div>What limitations in current state of the art is the probe addressing?</div></li></ul><p>The lack of proper chemical tools to differentiate the activity of CYP3A4 and CYP3A5 has led to the longstanding, yet erroneous, convention of treating the two enzymes as if they were one. Sometimes activity has been expressed as CYP3A to point out that the results are not specific for either CYP3A4 or CYP3A5. However, too often all activity has been contributed to CYP3A4. Furthermore, the practice of pooling tissue from multiple donors to generate an “average human” has given rise to the perception that CYP3A5 has less significance than CYP3A4. While it is certainly true that the abundance of CYP3A4 exceeds that of CYP3A5 in a multi-donor pool, this is not representative of actual patients. The concentrations of the two enzymes have been reported to be roughly equal in individuals that express CYP3A5 (<a class="bibr" href="#ml368.r1" rid="ml368.r1">1</a>).</p><ul><li class="half_rhythm"><div><i>What will the probe be used for?</i></div></li></ul><p>The identified probe and analogs will be useful for drug discovery projects, particularly safety pharmacology where the metabolic profile of new drugs are reported as part of the package submitted to FDA for new drug applications.</p><ul><li class="half_rhythm"><div><i>Who in the research community will use the probe?</i></div></li></ul><p>The probe is of significant use to the pharmaceutical industry and to researchers doing translational research. We have already sent the probe or the synthetic protocol to scientists at Pfizer, Bristol Meyers Squibb and Vanderbilt University who are now using the probe in their research.</p><ul><li class="half_rhythm"><div><i>What is the relevant biology to which the probe can be applied?</i></div></li></ul><p>The probe can be used to differentiate CYP3A4 and CYP3A5 activity in biological samples. This can be a source of significant variability because CYP3A5 has three common genetic alleles (<a class="bibr" href="#ml368.r2" rid="ml368.r2">2</a>). CYP3A5*1 leads to the expression of active, full length CYP3A5. The CYP3A5*3 (22893A→G) allele in intron 3 leads to a frame shift resulting in the majority of the CYP3A5 mRNA yielding inactive protein and loss of CYP3A5 expression. Analysis by Western blot and RT-PCR demonstrates that individuals homozygous for CYP3A5*3 have low levels of correctly spliced CYP3A5 mRNA and this corresponds to sharply lower CYP3A5 protein levels (<a class="bibr" href="#ml368.r2" rid="ml368.r2">2</a>). A second allele, CYP3A5*6 (30597G→A) on exon 7 causes the deletion of exon 7 from the splice variant and is associated with lower CYP3A5 catalytic activity. The clinical relevance of CYP3A5 genotype is seen with the immunosuppressant tacrolimus which is metabolized by CYP3A5 3-times more efficiently than by CYP3A4 (<a class="bibr" href="#ml368.r3" rid="ml368.r3">3</a>). In order to maintain the required tacrolimus trough concentrations of 5 to 15 ng/mL, patients that express active CYP3A5 (*1/*1 and *1/*3 genotype) require approximately twice the dose as *3/*3 (inactive splice variant) patients (<a class="bibr" href="#ml368.r4" rid="ml368.r4">4</a>). Additionally, CYP3A5 genotype has been implicated in vincristine metabolism where CYP3A5 low expressers were found to have increased risk of vincristine-induced neurotoxicity (<a class="bibr" href="#ml368.r5" rid="ml368.r5">5</a>-<a class="bibr" href="#ml368.r8" rid="ml368.r8">8</a>).</p></div><div id="ml368.s3"><h2 id="_ml368_s3_">1. Introduction</h2><p>The lack of proper chemical tools to differentiate the activity of CYP3A4 and CYP3A5 has led to the long-standing, yet erroneous, convention of treating the two enzymes as if they were one. Sometimes activity has been expressed as CYP3A to point out that the results are not specific for either CYP3A4 or CYP3A5. However, too often all activity has been attributed to CYP3A4. Furthermore, the practice of pooling tissue from multiple donors to generate an “average human” has given rise to the perception that CYP3A5 has less significance than CYP3A4. Although it is certainly true that the abundance of CYP3A4 exceeds that of CYP3A5 in a multidonor pool, this is not representative of actual patients. The concentrations of the two enzymes have been reported to be roughly equal in individuals who express CYP3A5 (<a class="bibr" href="#ml368.r9" rid="ml368.r9">9</a>). Enzyme-selective chemical inhibitors are commonly used in reaction phenotyping studies to determine the contribution of individual cytochrome P450 isoforms (<a class="bibr" href="#ml368.r10" rid="ml368.r10">10</a>). Knowledge of the metabolic pathway for a candidate compound allows more accurate predictions of potential drug-drug interactions. Quality chemical tools are available to determine the activity and inhibition of most of the major cytochromes P450 involved in xenobiotic metabolism. The commonly used CYP3A4 and CYP3A5 inhibitors inhibit both enzymes, precluding differentiation or activity in complex samples. Although no highly selective CYP3A4 or CYP3A5 inhibitors have been reported in the literature, several compounds have been shown to have modest 3- to 10-fold selectivity over CYP3A5 (<a class="bibr" href="#ml368.r11" rid="ml368.r11">11</a>,<a class="bibr" href="#ml368.r12" rid="ml368.r12">12</a>). This degree of selectivity is not sufficient to inhibit 90% of CYP3A4 without significant CYP3A5 inhibition. Despite the inability of these mildly selective inhibitors to serve as in vitro tools for the isolation of CYP3A5 activity, they demonstrate that a degree of selectivity is achievable across numerous structural classes. In general, CYP3A4 appears to be more susceptible to irreversible inactivation in the presence of compounds that are metabolized to reactive metabolites, and many of the published selective inhibitors are time dependent inhibitors (<a class="bibr" href="#ml368.r13" rid="ml368.r13">13</a>-<a class="bibr" href="#ml368.r15" rid="ml368.r15">15</a>). It should be stressed that many of the selective inactivators are not selective inhibitors because they display significant competitive inhibition of CYP3A5 despite their lack of time-dependent inactivation. CYP3A5 has three common genetic alleles (<a class="bibr" href="#ml368.r16" rid="ml368.r16">16</a>). CYP3A5*1 leads to the expression of active, full-length CYP3A5. The CYP3A5*3 (22893A3G) allele in intron 3 leads to a frameshift, resulting in the majority of the CYP3A5 mRNA yielding inactive protein and loss of CYP3A5 expression. Analysis by Western blot and RT-PCR demonstrates that individuals homozygous for CYP3A5*3 have low levels of correctly spliced CYP3A5 mRNA, and this corresponds to sharply lower CYP3A5 protein levels (<a class="bibr" href="#ml368.r16" rid="ml368.r16">16</a>). A second allele, CYP3A5*6 (30597G3A), on exon 7 causes the deletion of exon 7 from the splice variant and is associated with lower CYP3A5 catalytic activity. Selective inhibitors will refine the current prediction models for pharmacokinetic drug-drug interactions in which the catalytic efficiency of CYP3A4 and CYP3A5 can be accounted for and the influence of genetic polymorphisms can be incorporated in future models. A better understanding of both enzymes is important to make accurate clearance predictions before compounds are moved into human trials. The clinical relevance of the CYP3A5 genotype is seen with the immunosuppressant tacrolimus, which is metabolized by CYP3A5 3 times more efficiently than by CYP3A4 (<a class="bibr" href="#ml368.r17" rid="ml368.r17">17</a>). To maintain the required tacrolimus trough concentrations of 5 to 15 ng/ml, patients who express active CYP3A5 (*1/*1 and *1/*3 genotypes) require approximately twice the dose as patients with the *3/*3 (inactive splice variant) genotype (<a class="bibr" href="#ml368.r18" rid="ml368.r18">18</a>). In addition, the CYP3A5 genotype has been implicated in vincristine metabolism, and CYP3A5 low expressers were found to have an increased risk of vincristine-induced neurotoxicity (<a class="bibr" href="#ml368.r19" rid="ml368.r19">19</a>-<a class="bibr" href="#ml368.r22" rid="ml368.r22">22</a>). The current article details a highly selective CYP3A4 inhibitor suitable for isolation of CYP3A5 activity in human liver microsomes. We have published details of the structure-activity relationship of SR-9186 and a number of related analogs for selective CYP3A4 inhibition (<a class="bibr" href="#ml368.r23" rid="ml368.r23">23</a>). In this study, we put special emphasis on the use of the inhibitor under conditions encountered in conducting reaction phenotyping studies, such as high concentrations of microsomal protein and long incubation times. Specific recommendations are made for the use of this new tool compound.</p></div><div id="ml368.s4"><h2 id="_ml368_s4_">2. Materials and Methods</h2><p>All chemical reagents and solvents were acquired from commercial vendors. All assay protocols are reported in the relevant PubChem AIDs, provided below. Solubility, stability, and glutathione reactivity analyses were conducted in accordance with NIH guidelines. CYP450 inhibition and microsome stability analyses were performed as previously described.</p><div id="ml368.s5"><h3>2.1. Assays</h3><div id="ml368.s6"><h4>Probe Characterization Assays</h4><div id="ml368.s7"><h5>Vincristine M1 Formation in Genotyped Individual Donor Microsomes (AID 686944)</h5><p><b>Assay Overview:</b> The purpose of this assay is to determine if CYP3A5 activity could be “isolated” in human liver microsomes that contained both CYP3A4 and CYP3A5. Midazolam hydroxylation was used as a measure of total CYP3A4+3A5 activity and Vincristine M1 formation was used as an approximate marker of CYP3A5 activity as it is moderately selective for CYP3A5 (between 5-10-times greater activity with CYP3A5). Selective inhibitors were able to inhibit the CYP3A4 contribution to midazolam hydroxylation while allowing CYP3A5 to remain active. The correlation of midazolam hydroxylation and Vincristine M1 formation improved with selective inhibitors.</p><p>This assay preferentially monitors CYP3A5 activity by following the generation of the moderately selective Vincristine M1 metabolite. Approximately 20 human liver donors of known CYP3A5 genotype were compared. The donors were comprised of CYP3A5 *1/*1, *1/*3, and *3/*3 genotypes which have high, medium, and low CYP3A5 expression.</p><p><b>Protocol Summary:</b> Vincristine M1 formation in genotyped individual donor microsomes was evaluated with slight modification of established methods (<a class="bibr" href="#ml368.r19" rid="ml368.r19">19</a>, <a class="bibr" href="#ml368.r24" rid="ml368.r24">24</a>). Incubations containing 20 µM vincristine, 0.1 mg HLM protein/ml and 1 mM NADPH prepared in 100 mM potassium phosphate buffer, pH 7.4, were stopped after 15 min by the addition of an equal volume of acetonitrile containing 1 µM vinblastine as an internal standard. Analysis of vincristine M1 was by LC-MS/MS using a RP-amide column (Ascentis Express from Supelco, 2.7µm, 2.1*100mm) at 300uL/min with a 9 minute linear gradient elution from 85% A (water + 0.1% formic acid) to 80% B (acetonitrile + 0.1% formic acid).</p></div></div><div id="ml368.s8"><h4>Recombinant CYP Inhibition Assay: CYP3A4 and CYP3A5 (AID 686941)</h4><p><b>Assay Overview:</b> The purpose of this assay is to determine inhibitory activity of compounds against purified recombinantly expressed CYP3A4 and CYP3A5.</p><p>This assay monitors CYP3A4 and CYP3A5 activity using recombinantly expressed P450 purchased from BD-Biosciences. Activity was kinetic based following the hydroxylation of midazolam and testosterone via LC-MS/MS assays.</p><p><b>Protocol Summary:</b> Incubations utilizing recombinantly expressed P450 (BD Supersomes, BD Biosciences, Woburn, MA) were conducted similarly to what is described for HLM. Enzyme concentration for CYP3A4 and CYP3A5 incubations were 10 nM (2 pmole enzyme in 0.2 ml). Substrate concentrations were approximately equal to their respective Km. All incubations were prepared in 0.1 M potassium phosphate buffer, pH 7.4, and incubated at 37°C with shaking. Testosterone and midazolam are referred to as CYP3A substrates as they are metabolized in HLM by both CYP3A4 and CYP3A5. Analysis was by LC-MS/MS using an API4000 mass spectrometer (Applied Biosystems, Foster City, CA) interfaced with an Agilent 1200 HPLC (Agilent Technologies, Palo Alto, CA). In most cases chromatographic separation was achieved by using a Phenomenex Synergi Fusion RP C18 column (2.0 × 50 mm, 4 μm) with a mobile phase consisted of 0.1% aqueous formic acid (solvent-A) and acetonitrile with 0.1% formic acid (solvent-B) run at a constant flow rate of 0.375 ml/min. A 2.5 minute HPLC method was used with % B equal to 2% at t=0 min, 80% at t=1.35-1.6 min, and 2% at t=1.61-2.5 min (all gradients were linear).</p></div><div id="ml368.s9"><h4>Cytotoxicity Assays</h4><p>Cytotoxicity assays have not been done. The probe is not intended for <i>in vivo</i> use and the only cell that would be used is primary human hepatocytes in short incubations.</p></div></div><div id="ml368.s10"><h3>2.2. Probe Chemical Characterization</h3><p><sup>1</sup>H NMR (700 MHz, DMSO-<i>d</i><i><sub>6</sub></i>) <i>δ</i> (ppm) 9.05 (s, 1H), 9.02 (s, 1H), 8.49 (s, 1H), 8.09-8.06 (m, 3H), 7.90-7.86 (m, 4H), 7.81 (d, <i>J</i> = 8.4 Hz, 1H), 7.73 (d, <i>J</i> = 8.6 Hz, 2H), 7.63 (d, <i>J</i> = 8.6 Hz, 2H), 7.61 (d, <i>J</i> = 8.6 Hz, 2H);</p><p><sup>13</sup>C NMR (176 MHz, DMSO-<i>d</i><sub>6</sub>) <i>δ</i> (ppm) 152.3, 151.0, 144.3, 144.0, 140.5, 140.1, 132.9, 132.8, 131.3, 127.6, 127.2, 126.8, 119.0, 118.5, 118.2, 114.6, 109.2; LC-MS (M+H): 431.11.</p><p>Synthetic route. Probe chemical structure including stereochemistry. Separation of diastereomers (if necessary). Structure verification with 1H NMR and LCMS results. Solubility measure in phosphate buffered saline (PBS) at room temperature (23°C). PBS by definition is 137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic and a pH of 7.4. Stability measured at room temperature (23ºC) in PBS (no antioxidants or other protectants and DMSO concentration below 0.1%).</p><p><b><u>Compound Stability</u></b> - <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) was relatively stable in PBS. Compound levels decreased slightly over the 48 hours tested. There was a small decrease which corresponded to a 97-hour half-life. To test conditions similar to cell based incubations, stability was also demonstrated in DMEM media supplemented with 10% fetal bovine serum where a half-life of 121 hours was calculated. Based on these results it is not expected that there would be an issue working with the probe, but stock solutions should be freshly prepared. While the data is not shown, two 10 mM DMSO stock solutions (one approximately one year old and the second 2-months old) had equivalent levels of <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> to a freshly prepared stock. PBS stability of SR-7377, -8893, -8889, -8890, and -9038 were also tested and all had half-lives in PBS exceeding 48 hours.</p><div id="ml368.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK179830/bin/ml368f2a.jpg" alt="Figure 1. Stability of ML368." /></div><div class="graphic"><img src="/books/NBK179830/bin/ml368f2b.jpg" alt="Figure 1. Stability of ML368." /></div><h3><span class="label">Figure 1</span><span class="title">Stability of ML368</span></h3></div><p><b><u>Compound Solubility</u></b> – Solubility of <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) was determined to be 1.84 µM in PBS. Additionally the probe was found to extensively bind to plastic. For this reason intermediate dilution plates should be avoided. An example of an intermediate dilution plate would be where a small amount of compound is transferred from a DMSO stock (e.g. 1 µl) into a larger volume of an aqueous solution (e.g. 99 µl) to form an intermediate solution which is then transferred to the final incubation. Efforts should be made to make all dilutions in organic, which is directly added to the final incubation.</p><p><b><u>Glutathione Reactivity</u></b> – <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) was stable when 10 µM compound was incubated with 50 µM reduced glutathione over six hours. There was not difference between samples with and without glutathione.</p><div id="ml368.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Glutathione%20Reactivity%20of%20ML368.&p=BOOKS&id=179830_ml368f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK179830/bin/ml368f3.jpg" alt="Figure 2. Glutathione Reactivity of ML368." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Glutathione Reactivity of ML368</span></h3></div></div><div id="ml368.s11"><h3>2.3. Probe Preparations</h3><div id="ml368.s12"><h4>1-(4-(3<i>H</i>-imidazo[4,5-b]pyridin-7-yl)phenyl)-3-(4′-cyano-[1,1′-biphenyl]-4-yl)urea</h4><p>A solution of 4′-amino-[1,1′-biphenyl]-4-carbonitrile (0.097 g, 0.5 mmol) in EtOAc (3 mL) was added slowly over 10 min to a solution of triphosgene (0.148 g, 0.5 mmol) in EtOAC (3 mL) at 0>
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°C. The mixture was stirred at room temperature for 1 h and then heated to reflux for 4 h. The precipitate was filtered off and the solvent was evaporated to dryness to afford 4′-Isocyanato-[1,1′-biphenyl]-4-carbonitrile in quantitative yield.</p><p>To a solution of 4′-isocyanato-[1,1′-biphenyl]-4-carbonitrile (0.132 g, 0.6 mmol) in 1,2-dichloroethane (5 mL) was added 4-(3<i>H</i>-imidazo[4,5-b]pyridin-7-yl)aniline (0.105 g, 0.5 mmol) in DMSO (1 mL) dropwise. The reaction was heated to reflux overnight, cooled to room temperature, and solvent was evaporated. The residue was dissolved in DMF (5 mL) and submitted to preparative HPLC. The title compound was obtained as a brownish yellow solid (37%).</p><p>The following related analogs were synthesized following the same standard protocol as described for <a href="/pcsubstance/?term=ML#368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML#368</a> using 4-(3<i>H</i>-imidazo[4,5-b]pyridin-7-yl)aniline and the appropriate aryl isocyanate.</p></div><div id="ml368.s13"><h4>3-(3-(4-(3<i>H</i>-Imidazo[4,5-<i>b</i>]pyridin-7-yl)phenyl)ureido)-N-phenylbenzamide (SR-9038)</h4><p><sup>1</sup>H NMR (400 MHz, Methanol-<i>d<sub>4</sub></i>) <i>δ</i> (ppm) 9.34 (s, 1H), 8.32 (d, <i>J</i> = 8.7 Hz, 1H), 8.16-8.13 (m, 3H), 8.05 (t, J = 1.9 Hz, 1H), 7.74-7.67 (m, 5H), 7.61 (dt, <i>J</i> = 8.1, 1.4 Hz, 1H), 7.48 (t, <i>J</i> = 7.9 Hz, 1H), 7.41-7.37 (m, 2H), 7.19-7.15 (m, 1H). LC-MS (M+H)<sup>+</sup>: 449.12.</p><div id="ml368.f4" class="figure"><div class="graphic"><img src="/books/NBK179830/bin/ml368f4.jpg" alt="Image ml368f4" /></div></div></div><div id="ml368.s14"><h4>3-(3-(4-(3<i>H</i>-Imidazo[4,5-<i>b</i>]pyridin-7-yl)phenyl)ureido)-N-isopropylbenzamide (SR-7377)</h4><p><sup>1</sup>H NMR (400 MHz, Methanol-<i>d<sub>4</sub></i>) <i>δ</i> (ppm) 9.26 (br s, 1H), 8.33 (br s, 1H), 8.17-8.11 (m, 3H), 7.93-7.91 (m, 1H), 7.71-7.67 (m, 3H), 7.50-7.41 (m, 2H), 4.23 (sep, <i>J</i> = 6.6 Hz, 1H), 1.29 (d, <i>J</i> = 6.6 Hz, 6H). LC-MS (M+H)<sup>+</sup>: 415.15.</p><div id="ml368.f5" class="figure"><div class="graphic"><img src="/books/NBK179830/bin/ml368f5.jpg" alt="Image ml368f5" /></div></div></div><div id="ml368.s15"><h4>1-(4-(3<i>H</i>-Imidazo[4,5-<i>b</i>]pyridin-7-yl)phenyl)-3-(3-chlorophenyl)urea (SR-8889)</h4><p><sup>1</sup>H NMR (400 MHz, Methanol-<i>d<sub>4</sub></i>) <i>δ</i> (ppm) 9.38 (br s, 1H), 8.33 (d, <i>J</i> = 8.3 Hz, 1H), 8.15-8.11 (m, 3H), 7.68-7.63 (m, 3H), 7.30-7.26 (m, 2H), 7.03 (dt, <i>J</i> = 6.7, 2 Hz, 1H). LC-MS (M+H)<sup>+</sup>: 364.12.</p><div id="ml368.f6" class="figure"><div class="graphic"><img src="/books/NBK179830/bin/ml368f6.jpg" alt="Image ml368f6" /></div></div></div><div id="ml368.s16"><h4>Ethyl 3-(3-(4-(3<i>H</i>-Imidazo[4,5-<i>b</i>]pyridin-7-yl)phenyl)ureido)benzoate (SR-8893)</h4><p><sup>1</sup>H NMR (400 MHz, Methanol-<i>d<sub>4</sub></i>) <i>δ</i> (ppm) 9.26 (s, 1H), 8.29 (d, <i>J</i> = 8.7 Hz, 1H), 8.15 (t, <i>J</i> = 2.0 Hz, 1H), 8.14-8.10 (m, 3H), 7.74-7.69 (m, 2H), 7.66-7.63 (m, 2H), 7.24 (t, <i>J</i> = 8.0 Hz, 1H), 4.38 (q, <i>J</i> = 7.2 Hz, 2H), 1.41 (t, <i>J</i> = 7.2 Hz, 3H). LC-MS (M+H)<sup>+</sup>: 402.12.</p><div id="ml368.f7" class="figure"><div class="graphic"><img src="/books/NBK179830/bin/ml368f7.jpg" alt="Image ml368f7" /></div></div></div><div id="ml368.s17"><h4>1-(4-(3<i>H</i>-Imidazo[4,5-<i>b</i>]pyridin-7-yl)phenyl)-3-(4-chlorophenyl)urea (SR-8890)</h4><p><sup>1</sup>H NMR (400 MHz, Methanol-<i>d<sub>4</sub></i>) <i>δ</i> (ppm) 9.27 (br s, 1H), 8.30 (d, <i>J</i> = 8.6 Hz, 1H), 8.13-8.10 (m, 3H), 7.64-7.62 (m, 2H), 7.48-7.45 (m, 2H), 7.31-7.28 (m, 2H). LC-MS (M+H)<sup>+</sup>: 364.10.</p><div id="ml368.f8" class="figure"><div class="graphic"><img src="/books/NBK179830/bin/ml368f8.jpg" alt="Image ml368f8" /></div></div></div></div></div><div id="ml368.s18"><h2 id="_ml368_s18_">3. Results</h2><div id="ml368.f9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK179830/bin/ml368f9.jpg" alt="Figure 3. Selectivity of ML368." /></div><h3><span class="label">Figure 3</span><span class="title">Selectivity of ML368</span></h3></div><p><b>Selectivity under phenotyping conditions.</b> The effect of 1 µM ketoconazole or 2.5 µM <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) was evaluated in incubations containing 1 mg/ml HLM protein (150 donor mixed gender) using the marker substrates and substrate concentrations indicated in <a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a>. Incubation time was reduced to 1 minute. Inhibition of midazolam hydroxylation was similarly evaluated (B) in CYP3A5 *1/*1, *1/*3, and *3/*3 pooled microsomes (four individual donors mixed 1:1:1:1).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml368t2"><a href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml368t2" rid-ob="figobml368t2"><img class="small-thumb" src="/books/NBK179830/table/ml368.t2/?report=thumb" src-large="/books/NBK179830/table/ml368.t2/?report=previmg" alt="Table 1. P450 inhibition of substituted phenyl urea analogs." /></a><div class="icnblk_cntnt"><h4 id="ml368.t2"><a href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-ob="figobml368t2">Table 1</a></h4><p class="float-caption no_bottom_margin">P450 inhibition of substituted phenyl urea analogs. </p></div></div><div id="ml368.f10" class="figure bk_fig"><div class="graphic"><img src="/books/NBK179830/bin/ml368f10.jpg" alt="Figure 4. Inhibition of midazolam hydroxylation by ML368 (SR-9186) in genotyped individual donor human liver microsomes." /></div><h3><span class="label">Figure 4</span><span class="title">Inhibition of midazolam hydroxylation by ML368 (SR-9186) in genotyped individual donor human liver microsomes</span></h3></div><p><b>Inhibition of midazolam hydroxylation by <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) in genotyped individual donor human liver microsomes.</b> Triplicate incubations using individual donor microsomes were evaluated for formation of 1′-hydroxymidazolam. Data corresponding to *1/*1 donors (blue with a narrow dashed line), *1/*3 donors (orange with wider dashed line), and *3/*3 donors (black solid lines) were analyzed for changes in the observed IC<sub>50</sub> (Panel B) and for maximal inhibition (Panel C). Statistical analysis is a two-tailed unpaired t-test assuming unequal variance.</p><div id="ml368.s19"><h3>3.1. Summary of Screening Results</h3><p>The compounds were identified as part of the optimization of a different project. There was never a screen looking for CYP3A4 vs CYP3A5 selectivity.</p></div><div id="ml368.s20"><h3>3.2. Dose Response Curves for Probe</h3><p>IC<sub>50</sub> values for inhibition of midazolam→1′hydroxymidazolam, testosterone→6β-hydroxytestosterone, and vincristine→vincristine M1 9, 4, and 38 nM, respectively. Selectivity was demonstrated using recombinant CYP3A5 where <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> was a much weaker inhibitor. <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> did not inhibit any of the reactions by 50 percent when tested at concentrations up to 60 µM. When the CYP3A5 inhibition data was curve fit to a sigmoidal one-site competition model, inhibition constants of 7.4, 0.36, and 1.5 µM were calculated. The data is presented graphically.</p><div id="ml368.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Dose%20Response%20Curves%20for%20ML368.&p=BOOKS&id=179830_ml368f11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK179830/bin/ml368f11.jpg" alt="Figure 5. Dose Response Curves for ML368." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Dose Response Curves for ML368</span></h3></div><p><b>Selective inhibition of CYP3A4 vs. CYP3A5 by <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> in recombinant P450.</b> Triplicate incubations with <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186), 4 nM to 60 µM, were co-incubated with 1 mM NADPH, and 1 nM recombinant P450 in 100 mM phosphate buffer, pH 7.4. Probe substrates were 2.5 µM midazolam, 75 µM testosterone or 20 µM vincristine.</p></div><div id="ml368.s21"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>An initial set of analogs meant to explore what portions of the molecule were amenable to modification resulted in the discovery that the corresponding 4-substituted phenyl analogs <b>SR8890</b> and <b>4</b> showed similar IC<sub>50</sub>'s for CYP3A4 inhibition but had reduced CYP3A5 inhibition leading to increased selectivity (<a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a>). Given the improved CYP3A4/CYP3A5 selectivity in the phenyl urea series, structure activity relationship studies (SAR) were initiated on this scaffold. Compounds were easily synthesized as described in <b><a class="figpopup" href="/books/NBK179830/figure/ml368.f12/?report=objectonly" target="object" rid-figpopup="figml368f12" rid-ob="figobml368f12">Scheme 2</a></b>. The bromo imidazopyridine (<b>1</b>) was first protected with a p-methoxybenzyl group. This gave an inseparable mixture of protected regioisomers (only one shown for clarity), but the mixture could be carried forward without incident. The protected imidazopyridine underwent smooth Suzuki coupling to yield intermediate <b>2</b>. TFA deprotection and exposure to a variety of phenyl isocyanates afforded final products as solids.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml368f12" co-legend-rid="figlgndml368f12"><a href="/books/NBK179830/figure/ml368.f12/?report=objectonly" target="object" title="Scheme 2" class="img_link icnblk_img figpopup" rid-figpopup="figml368f12" rid-ob="figobml368f12"><img class="small-thumb" src="/books/NBK179830/bin/ml368f12.gif" src-large="/books/NBK179830/bin/ml368f12.jpg" alt="Scheme 2. (a) PMB-Br, K2CO3, DMAC; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(Ph3P)4, K2CO3, THF; (c) TFA; (d) RCNO, toluene." /></a><div class="icnblk_cntnt" id="figlgndml368f12"><h4 id="ml368.f12"><a href="/books/NBK179830/figure/ml368.f12/?report=objectonly" target="object" rid-ob="figobml368f12">Scheme 2</a></h4><p class="float-caption no_bottom_margin">(a) PMB-Br, K<sub>2</sub>CO<sub>3</sub>, DMAC; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(Ph<sub>3</sub>P)<sub>4</sub>, K<sub>2</sub>CO<sub>3</sub>, THF; (c) TFA; (d) RCNO, toluene. </p></div></div><p><b><a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a></b> summarizes the effects of substitution of the terminal phenyl ring upon inhibition of CYP3A4 and CYP3A5 activity using recombinant enzymes. <sup>6</sup> Substitution at all positions of the phenyl ring led to potent CYP3A4 inhibitors with varying degrees of selectivity against CYP3A5. 2- and 3- substituted analogs (<b>8</b>-<b>11</b>) showed reduced selectivity whereas larger 3-substituted analogs (<b>14</b>,<b>15</b>) showed improvement in selectivity for CYP3A4. 4-substituted analogs (<b>16</b>,<b>17</b>) also showed good levels of selectivity, however for <b>17</b>, precipitation at higher concentrations was observed. Given the good potency and nice selectivity profile of ester <b>15</b>, this compound was further analoged as shown in <b><a class="figpopup" href="/books/NBK179830/figure/ml368.f12/?report=objectonly" target="object" rid-figpopup="figml368f12" rid-ob="figobml368f12">Scheme 2</a></b>.</p><p>While esters <b>15</b> and <b>18</b> exhibited strong selectivity and potency for CYP3A4 vs CYP3A5, they were not pursued because of stability concerns. When tested in incubations containing 1 mg/ml human liver microsomes or human hepatic S9, the compounds had a half-life of approximately 8 minutes with or without the addition of NADPH indicating probably hydrolysis by hepatic esterases making <b>15</b> and <b>18</b> poor in vitro probes. Hence, amides were investigated as more stable surrogates. The parent ester was easily saponified, and a variety of amines were coupled to form the amides (<b>20</b>-<b>29</b>, <b><a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a></b>).</p><p>Several of the analogs were highly selective for the inhibition of CYP3A4 vs CYP3A5. A wide range of substituents were acceptable; however, larger substituents particularly with the disubstituted amides exhibited increased CYP3A5 inhibition, thus decreasing the fold-selectivity.</p><p>In order to evaluate the necessity of the imidazopyridine group, a variety of compounds were generated using compound <b>SR7377</b> as a template (<a class="figpopup" href="/books/NBK179830/table/ml368.t3/?report=objectonly" target="object" rid-figpopup="figml368t3" rid-ob="figobml368t3">Table 2</a>). Surprisingly, only SR <b>33</b> and SR</p><p><b>43</b> showed some CYP inhibition, however they were no longer selective. None of the other heterocycles investigated exhibited any appreciable CYP inhibition.</p><p>The most potent CYP3A4 inhibitor identified within the series was compound <b>17</b>; however, compound <b>17</b> suffered from poor solubility. SR <b>17</b> also wasn't the most selective inhibitor identified from this series, however it warranted further investigation. Hence, a series of substituted 4-phenyl analogs were prepared using similar strategies as in <a class="figpopup" href="/books/NBK179830/figure/ml368.f13/?report=objectonly" target="object" rid-figpopup="figml368f13" rid-ob="figobml368f13">Scheme 1</a> (<b>30</b>-<b>36</b>, <a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a>). 4-substituted biphenyl analogs (30-32) showed very good CYP3A4 inhibition and exquisite selectivity over CYP3A5. <b>SR9186</b> was the most potent CYP3A4 inhibitor identified and the most selective over CYP3A5 as well, and it if for this reason <b>SR9186</b> was chosen as the probe.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml368f13" co-legend-rid="figlgndml368f13"><a href="/books/NBK179830/figure/ml368.f13/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml368f13" rid-ob="figobml368f13"><img class="small-thumb" src="/books/NBK179830/bin/ml368f13.gif" src-large="/books/NBK179830/bin/ml368f13.jpg" alt="Scheme 1. Synthesis of ML368 (SR-9186)." /></a><div class="icnblk_cntnt" id="figlgndml368f13"><h4 id="ml368.f13"><a href="/books/NBK179830/figure/ml368.f13/?report=objectonly" target="object" rid-ob="figobml368f13">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML368 (SR-9186). </p></div></div></div><div id="ml368.s22"><h3>3.4. SAR Tables</h3><p>20-30 analogs derivatized at more than two distinct positions of the molecule) to improve potency/selectivity and provide initial SAR that substantiates the specific probe activities on the target/pathway. A graphic, showing sample SAR Table (including Label and Title), is shown in <b><a class="figpopup" href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object" rid-figpopup="figml368t2" rid-ob="figobml368t2">Table 1</a></b>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml368t3"><a href="/books/NBK179830/table/ml368.t3/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml368t3" rid-ob="figobml368t3"><img class="small-thumb" src="/books/NBK179830/table/ml368.t3/?report=thumb" src-large="/books/NBK179830/table/ml368.t3/?report=previmg" alt="Table 2. Imidazopyridine derivatives of compound SR7377." /></a><div class="icnblk_cntnt"><h4 id="ml368.t3"><a href="/books/NBK179830/table/ml368.t3/?report=objectonly" target="object" rid-ob="figobml368t3">Table 2</a></h4><p class="float-caption no_bottom_margin">Imidazopyridine derivatives of compound SR7377. </p></div></div></div><div id="ml368.s23"><h3>3.5. Cellular Activity</h3><p>Preliminary experiments have shown that <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> (SR-9186) inhibits testosterone and midazolam hydroxylation in human hepatocytes, but detailed studies have not been conducted.</p></div><div id="ml368.s24"><h3>3.6. Profiling Assays</h3><p>Compounds have not been profiled in commercial selectivity assays.</p></div></div><div id="ml368.s25"><h2 id="_ml368_s25_">4. Discussion</h2><p>Cytochrome P450 are the major family of enzymes responsible for the oxidative metabolism of pharmaceuticals and xenobiotics. CYP3A4 and CYP3A5 have been shown to have overlapping substrate and inhibitor profiles and their inhibition has been demonstrated to be involved in numerous pharmacokinetic drug-drug interactions. Here we report the first highly selective CYP3A4 inhibitor optimized from an initial lead with ≈30-fold selectivity over CYP3A5 to yield a series of compounds with greater than 1000-fold selectivity. The lack of proper chemical tools to differentiate the activity of CYP3A4 and CYP3A5 has led to the longstanding, yet erroneous, convention of treating the two enzymes as if they were one. Sometimes activity has been expressed as CYP3A to point out that the results are not specific for either CYP3A4 or CYP3A5. However, too often all activity has been contributed to CYP3A4. Furthermore, the practice of pooling tissue from multiple donors to generate an “average human” has given rise to the perception that CYP3A5 has less significance than CYP3A4. While it is certainly true that the abundance of CYP3A4 exceeds that of CYP3A5 in a multi-donor pool, this is not representative of actual patients. The concentrations of the two enzymes have been reported to be roughly equal in individuals that express CYP3A5 (<a class="bibr" href="#ml368.r1" rid="ml368.r1">1</a>). The current manuscript details a highly selective CYP3A4 inhibitor suitable for isolation of CYP3A5 activity in human liver microsomes. We have published details of the structure activity relationship of <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> and a number of related analogs for selective CYP3A4 inhibition (<a class="bibr" href="#ml368.r23" rid="ml368.r23">23</a>).</p><div id="ml368.s26"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>Only a handful of compounds are known to have a significant (>5-fold) preference for CYP3A4 vs. CYP3A5, either as a substrate or as an inhibitor. This is likely because few compounds have been examined for differences and what data does exist is largely unreported. With the recent trend in the pharmaceutical industry to minimize the potential for drug-drug interactions by moving away from CYP3A4 substrates and inhibitors, it is possible that we will inadvertently see an increased number of CYP3A5-biased inhibitors which would not have been recognized as potent inhibitors using traditional methodologies of pooled HLM and pan-substrates such as midazolam or testosterone.</p><p>We believe that <a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> is an exciting new <i>in vitro</i> chemical tool for the differentiation of CYP3A4 and CYP3A5 activities. The massive costs required to demonstrate human safety for a compound without therapeutic benefit would make it naïve to propose designing a CYP3A4 selective <i>in vivo</i> inhibitor. However, as appropriate chemical tools are developed to clearly differentiate CYP3A4 and CYP3A5 activity, approved drugs with sufficient selectivity to help elucidate the individual contributions of the two enzymes <i>in vivo</i> may be discovered.</p><p><a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a> is the first compound that can differentiate the contributions of CYP3A4 and CYP3A5. The presented data has been focused upon a reaction phenotyping application. Such experiments typically utilize high concentrations of hepatic microsomes and long incubation times. To have utility in phenotyping experiments the inhibitor must be irreversible or have sufficient metabolic stability that the inhibition is maintained over the entire incubation. SR-9186 concentrations were minimally effected in HLM incubations and it had a microsomal half-life similar to that of ketoconazole.</p></div><div id="ml368.s27"><h3>4.2. Mechanism of Action Studies</h3><p>Studies were conducted to evaluate the use of the new probes for differentiating CYP3A4 and CYP3A5 in human liver microsomes. The compound is the first highly selective CYP3a4 inhibitor that is able to “isolate” cyp3A5 activity through the potent inhibition of CYP3A4 while having minimal effect on CYP3A5 catalyzed reactions. Detailed methods and results can be found within this reference (<a class="bibr" href="#ml368.r25" rid="ml368.r25">25</a>).</p></div><div id="ml368.s28"><h3>4.3. Planned Future Studies</h3><p>There are no current plans to further refine the selective inhibitor. However, the compound is being used internally at Scripps to study CYP3A biology. We have also heard from Bristol Meyers Squibb and Pfizer that they have synthesized the compound for evaluation in their internal drug discovery and drug safety groups.</p></div></div><div id="ml368.s29"><h2 id="_ml368_s29_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml368.r1">Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. <span><span class="ref-journal">Mol Pharmacol. </span>2002;<span class="ref-vol">62</span>:162–172.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12065767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12065767</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml368.r2">Leskela S, Honrado E, Montero-Conde C, Landa I, Cascon A, Leton R, Talavera P, Cozar JM, Concha A, Robledo M, Rodriguez-Antona C. Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer. <span><span class="ref-journal">Endocr Relat Cancer. </span>2007;<span class="ref-vol">14</span>:645–654.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17914095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17914095</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml368.r3">Barry A, Levine M. A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. <span><span class="ref-journal">Ther Drug Monit. </span>2010;<span class="ref-vol">32</span>:708–714.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20864901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20864901</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml368.r4">Zhao Y, Song M, Guan D, Bi S, Meng J, Li Q, Wang W. Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus. <span><span class="ref-journal">Transplant Proc. </span>2005;<span class="ref-vol">37</span>:178–181.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15808586" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15808586</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml368.r5">Dennison JB, Jones DR, Renbarger JL, Hall SD. Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2007;<span class="ref-vol">321</span>:553–563.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17272675" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17272675</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml368.r6">Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD. Selective metabolism of vincristine in vitro by CYP3A5. <span><span class="ref-journal">Drug Metab Dispos. </span>2006;<span class="ref-vol">34</span>:1317–1327.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16679390" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16679390</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml368.r7">Dennison JB, Mohutsky MA, Barbuch RJ, Wrighton SA, Hall SD. Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2008;<span class="ref-vol">327</span>:248–257.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18650247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18650247</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml368.r8">Egbelakin A, Ferguson MJ, MacGill EA, Lehmann AS, Topletz AR, Quinney SK, Li L, McCammack KC, Hall SD, Renbarger JL. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. <span><span class="ref-journal">Pediatr Blood Cancer. </span>2011;<span class="ref-vol">56</span>:361–367.</span> [<a href="/pmc/articles/PMC3020258/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3020258</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21225912" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21225912</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml368.r9">Lin YS, Dowling AL, Quigley SD, Farin FM, Zhang J, Lamba J, Schuetz EG, Thummel KE. Co-regulation of CYP3A4 and CYP3A5 and contribution to hepatic and intestinal midazolam metabolism. <span><span class="ref-journal">Mol Pharmacol. </span>2002;<span class="ref-vol">62</span>:162–172.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12065767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12065767</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml368.r10">Clarke SE. In vitro assessment of human cytochrome P450. <span><span class="ref-journal">Xenobiotica. </span>1998;<span class="ref-vol">28</span>:1167–1202.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9890158" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9890158</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml368.r11">Rendic S. Summary of information on human CYP enzymes: human P450 metabolism data. <span><span class="ref-journal">Drug Metab Rev. </span>2002;<span class="ref-vol">34</span>:83–448.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11996015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11996015</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml368.r12">Soars MG, Grime K, Riley RJ. Comparative analysis of substrate and inhibitor interactions with CYP3A4 and CYP3A5. <span><span class="ref-journal">Xenobiotica. </span>2006;<span class="ref-vol">36</span>:287–299.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16684709" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16684709</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml368.r13">Khan KK, He YQ, Correia MA, Halpert JR. Differential oxidation of mifepristone by cytochromes P450 3A4 and 3A5: selective inactivation of P450 3A4. <span><span class="ref-journal">Drug Metab Dispos. </span>2002;<span class="ref-vol">30</span>:985–990.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12167563" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12167563</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml368.r14">Stresser DM, Broudy MI, Ho T, Cargill CE, Blanchard AP, Sharma R, Dandeneau AA, Goodwin JJ, Turner SD, Erve JC, et al. Highly selective inhibition of human CYP3Aa in vitro by azamulin and evidence that inhibition is irreversible. <span><span class="ref-journal">Drug Metab Dispos. </span>2004;<span class="ref-vol">32</span>:105–112.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14709627" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14709627</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml368.r15">Pearson JT, Wahlstrom JL, Dickmann LJ, Kumar S, Halpert JR, Wienkers LC, Foti RS, Rock DA. Differential time-dependent inactivation of P450 3A4 and P450 3A5 by raloxifene: a key role for C239 in quenching reactive intermediates. <span><span class="ref-journal">Chem Res Toxicol. </span>2007;<span class="ref-vol">20</span>:1778–1786.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18001057" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18001057</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml368.r16">Leskelä S, Honrado E, Montero-Conde C, Landa I, Casco´n A, Leto´n R, Talavera P, Co´zar JM, Concha A, Robledo M, et al. Cytochrome P450 3A5 is highly expressed in normal prostate cells but absent in prostate cancer. <span><span class="ref-journal">Endocr Relat Cancer. </span>2007;<span class="ref-vol">14</span>:645–654.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17914095" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17914095</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml368.r17">Barry A, Levine M. A systematic review of the effect of CYP3A5 genotype on the apparent oral clearance of tacrolimus in renal transplant recipients. <span><span class="ref-journal">Ther Drug Monit. </span>2010;<span class="ref-vol">32</span>:708–714.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20864901" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20864901</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml368.r18">Zhao Y, Song M, Guan D, Bi S, Meng J, Li Q, Wang W. Genetic polymorphisms of CYP3A5 genes and concentration of the cyclosporine and tacrolimus. <span><span class="ref-journal">Transplant Proc. </span>2005;<span class="ref-vol">37</span>:178–181.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15808586" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15808586</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml368.r19">Dennison JB, Jones DR, Renbarger JL, Hall SD. Effect of CYP3A5 expression on vincristine metabolism with human liver microsomes. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2007;<span class="ref-vol">321</span>:553–563.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17272675" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17272675</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml368.r20">Dennison JB, Kulanthaivel P, Barbuch RJ, Renbarger JL, Ehlhardt WJ, Hall SD. Selective metabolism of vincristine in vitro by CYP3A5. <span><span class="ref-journal">Drug Metab Dispos. </span>2006;<span class="ref-vol">34</span>:1317–1327.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16679390" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16679390</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml368.r21">Dennison JB, Mohutsky MA, Barbuch RJ, Wrighton SA, Hall SD. Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2008;<span class="ref-vol">327</span>:248–257.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18650247" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18650247</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml368.r22">Egbelakin A, Ferguson MJ, MacGill EA, Lehmann AS, Topletz AR, Quinney SK, Li L, McCammack KC, Hall SD, Renbarger JL. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. <span><span class="ref-journal">Pediatr Blood Cancer. </span>2011;<span class="ref-vol">56</span>:361–367.</span> [<a href="/pmc/articles/PMC3020258/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3020258</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21225912" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21225912</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml368.r23">Song X, Li X, Ruiz CH, Yin Y, Feng Y, Kamenecka TM, Cameron MD. Imidazopyridines as selective CYP3A4 inhibitors. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2012;<span class="ref-vol">22</span>:1611–1614.</span> [<a href="/pmc/articles/PMC4481867/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4481867</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22264486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22264486</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml368.r24">Dennison JB, Renbarger JL, Walterhouse DO, Jones DR, Hall SD. Quantification of vincristine and its major metabolite in human plasma by high-performance liquid chromatography/tandem mass spectrometry. <span><span class="ref-journal">Ther Drug Monit. </span>2008;<span class="ref-vol">30</span>:357–364.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18520608" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18520608</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml368.r25">Li X, Song X, Kamenecka TM, Cameron MD. Discovery of a Highly Selective CYP3A4 Inhibitor Suitable for Reaction Phenotyping Studies and Differentiation of CYP3A4 and CYP3A5. <span><span class="ref-journal">Drug Metab Dispos. </span>2012 Sep;<span class="ref-vol">40</span>(9):1803–9.</span> [<a href="/pmc/articles/PMC3422543/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3422543</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22696420" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22696420</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK179830_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Michael Cameron</span>,<sup>1</sup> <span itemprop="author">Ted Kamenecka</span>,<sup>1</sup> <span itemprop="author">Franck Madoux</span>,<sup>2</sup> <span itemprop="author">Peter Chase</span>,<sup>2</sup> <span itemprop="author">William Roush</span>,<sup>3</sup> <span itemprop="author">Peter Hodder</span>,<sup>1,2</sup> and <span itemprop="author">Patrick R. Griffin</span><sup>1</sup><sup>,5</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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The Scripps Research Institute, Department of Molecular Therapeutics, Jupiter, FL;</div><div class="affiliation"><sup>2</sup>
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The Scripps Research Institute, Lead Identification Division, Jupiter, FL;</div><div class="affiliation"><sup>3</sup>
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The Scripps Research Institute, Department of Chemistry, Jupiter, FL;</div><div class="affiliation">
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<sup>5</sup> Corresponding author:
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.sppircs@niffirgp" class="oemail">ude.sppircs@niffirgp</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 15, 2013</span>; Last Update: <span itemprop="dateModified">September 18, 2014</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Cameron M, Kamenecka T, Madoux F, et al. ML368 Identification of Imidazopyridines as Selective Inhibitors of the Cytochrome P450 Enzyme CYP3A4. 2013 Apr 15 [Updated 2014 Sep 18]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml369/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml367/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml368f1"><div id="ml368.f1" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml368f1&p=BOOKS&id=179830_ml368f1.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK179830/bin/ml368f1.jpg" alt="Image ml368f1" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="table-wrap" id="figobml368t1"><div id="ml368.t1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK179830/table/ml368.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml368.t1_lrgtbl__"><table><thead><tr><th id="hd_h_ml368.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML#</th><th id="hd_h_ml368.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml368.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml368.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target</th><th id="hd_h_ml368.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml368.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective</th><th id="hd_h_ml368.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name: IC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml368.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 71295818/<a href="/pcsubstance/?term=ML368[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML368</a></td><td headers="hd_h_ml368.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CYP3A4</td><td headers="hd_h_ml368.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Midazolam → 1′hydroxymidazolam 9 nM<br /><br />testosterone→6β-hydroxytestosterone 4 nM<br /><br />vincristine → vincristine M138 nM<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008189" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 162008189</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686941" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686941</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686944" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686944</a>] Active</td><td headers="hd_h_ml368.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CYP3A5</td><td headers="hd_h_ml368.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Midazolam → 1′hydroxymidazolam >60,000 nM<br /><br />testosterone→6β-hydroxytestosterone >60,000 nM<br /><br />vincristine → vincristine M1 >60,000 nM<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008189" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 162008189</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686941" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686941</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686944" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686944</a>] Active</td><td headers="hd_h_ml368.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2000x or higher depending on substrate</td><td headers="hd_h_ml368.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml368f2"><div id="ml368.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f2a.jpg" alt="Figure 1. Stability of ML368." /></div><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f2b.jpg" alt="Figure 1. Stability of ML368." /></div><h3><span class="label">Figure 1</span><span class="title">Stability of ML368</span></h3></div></article><article data-type="fig" id="figobml368f3"><div id="ml368.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Glutathione%20Reactivity%20of%20ML368.&p=BOOKS&id=179830_ml368f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK179830/bin/ml368f3.jpg" alt="Figure 2. Glutathione Reactivity of ML368." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Glutathione Reactivity of ML368</span></h3></div></article><article data-type="fig" id="figobml368f4"><div id="ml368.f4" class="figure"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f4.jpg" alt="Image ml368f4" /></div></div></article><article data-type="fig" id="figobml368f5"><div id="ml368.f5" class="figure"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f5.jpg" alt="Image ml368f5" /></div></div></article><article data-type="fig" id="figobml368f6"><div id="ml368.f6" class="figure"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f6.jpg" alt="Image ml368f6" /></div></div></article><article data-type="fig" id="figobml368f7"><div id="ml368.f7" class="figure"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f7.jpg" alt="Image ml368f7" /></div></div></article><article data-type="fig" id="figobml368f8"><div id="ml368.f8" class="figure"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f8.jpg" alt="Image ml368f8" /></div></div></article><article data-type="fig" id="figobml368f9"><div id="ml368.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f9.jpg" alt="Figure 3. Selectivity of ML368." /></div><h3><span class="label">Figure 3</span><span class="title">Selectivity of ML368</span></h3></div></article><article data-type="table-wrap" id="figobml368t2"><div id="ml368.t2" class="table"><h3><span class="label">Table 1</span><span class="title">P450 inhibition of substituted phenyl urea analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK179830/table/ml368.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml368.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml368.t2_1_1_1_1" colspan="7" rowspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu1.jpg" alt="Image ml368fu1.jpg" /></div></th></tr><tr><th headers="hd_h_ml368.t2_1_1_1_1" id="hd_h_ml368.t2_1_1_2_1" colspan="7" rowspan="1" style="vertical-align:bottom;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1" id="hd_h_ml368.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1" id="hd_h_ml368.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1" id="hd_h_ml368.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1" id="hd_h_ml368.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1" id="hd_h_ml368.t2_1_1_3_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">enzyme IC<sub>50</sub> (µM)<sup>a</sup><sup>,</sup><sup>b</sup></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" id="hd_h_ml368.t2_1_1_3_6" rowspan="3" colspan="1" style="text-align:center;vertical-align:middle;">Fold-Selective</th></tr><tr><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1" id="hd_h_ml368.t2_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2" id="hd_h_ml368.t2_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3" id="hd_h_ml368.t2_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4" id="hd_h_ml368.t2_1_1_4_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5" id="hd_h_ml368.t2_1_1_4_5" colspan="2" rowspan="1" style="vertical-align:bottom;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1" id="hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR#</th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2" id="hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3" id="hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4" id="hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5" id="hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CYP3A4</th><th headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5" id="hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CYP3A5</th></tr></thead><tbody><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8890</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008149" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008149</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57400522</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Cl</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.31</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>190</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8923</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008166" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008166</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57402329</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Br</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.21</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">60</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">290</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8888</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008147" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008147</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>162008147</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2-Cl</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.60</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.1</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8896</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008155" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008155</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57391850</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-F</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">.71</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11.4</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">16</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8889</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008148" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008148</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57391851</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-Cl</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.48</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">52</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">110</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8920</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008163" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008163</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57404044</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-Br</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.092</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11.4</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">124</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8891</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008150" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008150</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57391852</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.2</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">37</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8898</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008157" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008157</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57398846</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-Me</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.5</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>40</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8921</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008164" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008164</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57393587</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-NO<sub>2</sub></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.061</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31.5</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">518</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8892</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008151" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008151</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57397067</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CO<sub>2</sub>Me</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.082</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>700</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8924</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008167" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008167</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57393588</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-OMe</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.20</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">39%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>300</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8922</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008165" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008165</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295800</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Ph</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.026</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">27% <i><sup>c</sup></i></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>80<i><sup>c</sup></i></td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8893</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008152" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008152</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57393589</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CO<sub>2</sub>Et</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.044</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">27%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>1300</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8894</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008153" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008153</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57398847</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CO<sub>2</sub>H</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">39%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">33%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">None</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9035</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008176" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008176</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57397068</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONHMe</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.098</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>600</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9036</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008177" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008177</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57404045</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONHEt</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.055</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20.3</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">368</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7377</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008145</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295820</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONHiPr</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.090</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">41%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>600</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9039</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008180" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008180</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57400523</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONMe<sub>2</sub></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.11</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">60</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">544</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9040</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008181" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008181</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57395300</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONEt<sub>2</sub></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.047</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.6</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">183</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9041</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008182" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008182</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57400524</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONiPr<sub>2</sub></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.060</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.6</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9038</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008179" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008179</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57404046</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONHPh</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.053</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>1100</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9037</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008178" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008178</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57398848</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-CONHcyclopentyl</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.070</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.9</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">98</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9042</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008183" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008183</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57395301</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-COpiperidine</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.079</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.5</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">70</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9043</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008184" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008184</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57391853</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3-COmorpholine</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.29</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">60</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">208</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9186</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008189" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008189</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295818</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Ph-4′-CN</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.011</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">33</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3000</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9188</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008190" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008190</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295788</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Ph-4′-OH</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.030</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">700</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9189</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008191" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008191</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295808</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Ph-4′-CONH<sub>2</sub></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.20<sup>b</sup></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>300<i><sup>c</sup></i></td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9190</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008192" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008192</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295819</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-Ph-3′-OMe</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.048</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.8</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">143</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9185</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008188" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008188</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295796</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">naphthyl <sup>b</sup></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.7</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9191</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008193" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008193</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295809</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">pyridin-3-yl <sup>b</sup></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.22</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>270</td></tr><tr><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_1 hd_h_ml368.t2_1_1_4_1 hd_h_ml368.t2_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9192</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_2 hd_h_ml368.t2_1_1_4_2 hd_h_ml368.t2_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008194" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008194</a></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_3 hd_h_ml368.t2_1_1_4_3 hd_h_ml368.t2_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>71295812</b></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_4 hd_h_ml368.t2_1_1_4_4 hd_h_ml368.t2_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">pyridin-4-yl <sup>b</sup></td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.36</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_5 hd_h_ml368.t2_1_1_4_5 hd_h_ml368.t2_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29%</td><td headers="hd_h_ml368.t2_1_1_1_1 hd_h_ml368.t2_1_1_2_1 hd_h_ml368.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>160</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml368.tfn1"><p class="no_margin">Values are mean of two or more experiments using midazolam hydroxylation as a measure or CYP3A4/5 activity. The error in these values is within ±30% of the mean;</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml368.tfn2"><p class="no_margin">Phenyl was replaced with naphthylene and pyridine</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml368f10"><div id="ml368.f10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK179830/bin/ml368f10.jpg" alt="Figure 4. Inhibition of midazolam hydroxylation by ML368 (SR-9186) in genotyped individual donor human liver microsomes." /></div><h3><span class="label">Figure 4</span><span class="title">Inhibition of midazolam hydroxylation by ML368 (SR-9186) in genotyped individual donor human liver microsomes</span></h3></div></article><article data-type="fig" id="figobml368f11"><div id="ml368.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Dose%20Response%20Curves%20for%20ML368.&p=BOOKS&id=179830_ml368f11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK179830/bin/ml368f11.jpg" alt="Figure 5. Dose Response Curves for ML368." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Dose Response Curves for ML368</span></h3></div></article><article data-type="fig" id="figobml368f12"><div id="ml368.f12" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%202.%20(a)%20PMB-Br%2C%20K2CO3%2C%20DMAC%3B%20(b)%204-(4%2C4%2C5%2C5-tetramethyl-1%2C3%2C2-dioxaborolan-2-yl)aniline%2C%20Pd(Ph3P)4%2C%20K2CO3%2C%20THF%3B%20(c)%20TFA%3B%20(d)%20RCNO%2C%20toluene.&p=BOOKS&id=179830_ml368f12.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK179830/bin/ml368f12.jpg" alt="Scheme 2. (a) PMB-Br, K2CO3, DMAC; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(Ph3P)4, K2CO3, THF; (c) TFA; (d) RCNO, toluene." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 2</span><span class="title">(a) PMB-Br, K<sub>2</sub>CO<sub>3</sub>, DMAC; (b) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline, Pd(Ph<sub>3</sub>P)<sub>4</sub>, K<sub>2</sub>CO<sub>3</sub>, THF; (c) TFA; (d) RCNO, toluene</span></h3></div></article><article data-type="fig" id="figobml368f13"><div id="ml368.f13" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Scheme%201.%20Synthesis%20of%20ML368%20(SR-9186).&p=BOOKS&id=179830_ml368f13.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK179830/bin/ml368f13.jpg" alt="Scheme 1. Synthesis of ML368 (SR-9186)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML368 (SR-9186)</span></h3></div></article><article data-type="table-wrap" id="figobml368t3"><div id="ml368.t3" class="table"><h3><span class="label">Table 2</span><span class="title">Imidazopyridine derivatives of compound SR7377</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK179830/table/ml368.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml368.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml368.t3_1_1_1_1" colspan="7" rowspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu2.jpg" alt="Image ml368fu2.jpg" /></div></th></tr><tr><th headers="hd_h_ml368.t3_1_1_1_1" id="hd_h_ml368.t3_1_1_2_1" colspan="7" rowspan="1" style="vertical-align:bottom;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">enzyme IC<sub>50</sub> (µM)<sup>a</sup></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1" id="hd_h_ml368.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold-Selective</th></tr><tr><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1" id="hd_h_ml368.t3_1_1_4_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2" id="hd_h_ml368.t3_1_1_4_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3" id="hd_h_ml368.t3_1_1_4_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4" id="hd_h_ml368.t3_1_1_4_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5" id="hd_h_ml368.t3_1_1_4_5" colspan="2" rowspan="1" style="vertical-align:bottom;">
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<span class="hr"></span></th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6" id="hd_h_ml368.t3_1_1_4_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th></tr><tr><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1" id="hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SR#</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2" id="hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3" id="hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4" id="hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5" id="hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CYP3A4</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5" id="hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CYP3A5</th><th headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6" id="hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th></tr></thead><tbody><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7377</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008145</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295820</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu3.jpg" alt="Image ml368fu3.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.090</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>650</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7127</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008199" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008199</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295831</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu4.jpg" alt="Image ml368fu4.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.56</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">61</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7734</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008208" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008208</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295828</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu5.jpg" alt="Image ml368fu5.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.9</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>21</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7454</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008203" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008203</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295826</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu6.jpg" alt="Image ml368fu6.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7681</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008207" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008207</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295833</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu7.jpg" alt="Image ml368fu7.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.6</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.1</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7453</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008202" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008202</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295830</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu8.jpg" alt="Image ml368fu8.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7485</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008204" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008204</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295822</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu9.jpg" alt="Image ml368fu9.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">36%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7128</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008200" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008200</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295824</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu10.jpg" alt="Image ml368fu10.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7376</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/162008201" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">162008201</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>71295834</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu11.jpg" alt="Image ml368fu11.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">33%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8%</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">None</td></tr><tr><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_1 hd_h_ml368.t3_1_1_4_1 hd_h_ml368.t3_1_1_5_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7126</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_2 hd_h_ml368.t3_1_1_4_2 hd_h_ml368.t3_1_1_5_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/43" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">43</a></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_3 hd_h_ml368.t3_1_1_4_3 hd_h_ml368.t3_1_1_5_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>43</b></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_4 hd_h_ml368.t3_1_1_4_4 hd_h_ml368.t3_1_1_5_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK179830/bin/ml368fu12.jpg" alt="Image ml368fu12.jpg" /></div></td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.13</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_5 hd_h_ml368.t3_1_1_4_5 hd_h_ml368.t3_1_1_5_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.98</td><td headers="hd_h_ml368.t3_1_1_1_1 hd_h_ml368.t3_1_1_2_1 hd_h_ml368.t3_1_1_3_6 hd_h_ml368.t3_1_1_4_6 hd_h_ml368.t3_1_1_5_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml368.tfn3"><p class="no_margin">Values are means of two or more experiments. The error in these values is within ±30% of the mean.</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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