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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Cardioprotective inhibitors of reperfusion injury - 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="Cardioprotective inhibitors of reperfusion injury">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/03/22">
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<meta name="citation_author" content="Ada Kane">
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<meta name="citation_author" content="Satyamaheshwar Peddibhotla">
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<meta name="citation_author" content="Patrick Maloney">
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<meta name="citation_author" content="Alka Mehta">
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<meta name="citation_author" content="Becky Hood">
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<meta name="citation_author" content="Eigo Suyama">
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<meta name="citation_author" content="Kevin Nguyen">
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<meta name="citation_author" content="Stefan Vasile">
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<meta name="citation_author" content="Laurel Leavitt">
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<meta name="citation_author" content="Anton Cheltsov">
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<meta name="citation_author" content="Sumeet Salaiwal">
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<meta name="citation_author" content="Derek Stonich">
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<meta name="citation_author" content="Arianna Mangravita-Novo">
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<meta name="citation_author" content="Michael Vicchiarelli">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Jena Diwan">
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<meta name="citation_author" content="Thomas D.Y. Chung">
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<meta name="citation_author" content="Anthony B. Pinkerton">
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<meta name="citation_author" content="Paul Hershberger">
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<meta name="citation_author" content="Siobhan Malany">
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<meta name="citation_author" content="Richard N. Kitsis">
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<meta name="citation_pmid" content="24404634">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK174883/">
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<meta name="DC.Title" content="Cardioprotective inhibitors of reperfusion injury">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Ada Kane">
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<meta name="DC.Contributor" content="Satyamaheshwar Peddibhotla">
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<meta name="DC.Contributor" content="Patrick Maloney">
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<meta name="DC.Contributor" content="Alka Mehta">
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<meta name="DC.Contributor" content="Becky Hood">
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<meta name="DC.Contributor" content="Eigo Suyama">
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<meta name="DC.Contributor" content="Kevin Nguyen">
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<meta name="DC.Contributor" content="Stefan Vasile">
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<meta name="DC.Contributor" content="Laurel Leavitt">
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<meta name="DC.Contributor" content="Anton Cheltsov">
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<meta name="DC.Contributor" content="Sumeet Salaiwal">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Arianna Mangravita-Novo">
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<meta name="DC.Contributor" content="Michael Vicchiarelli">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Jena Diwan">
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<meta name="DC.Contributor" content="Thomas D.Y. Chung">
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<meta name="DC.Contributor" content="Anthony B. Pinkerton">
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<meta name="DC.Contributor" content="Paul Hershberger">
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<meta name="DC.Contributor" content="Siobhan Malany">
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<meta name="DC.Contributor" content="Richard N. Kitsis">
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<meta name="DC.Date" content="2013/03/22">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK174883/">
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<meta name="description" content="An understanding of the mechanisms and pathways that mediate cardiac myocyte death is critical for the development of pharmacological therapies to limit heart damage during myocardial infarction (“heart attack”). We have completed the first unbiased cell-based screen of the MLSMR library consisting of ~360,000 compounds to identify small molecule probes that protect cardiac myocytes against oxidative and metabolic stresses, both precipitants of cell death during myocardial infarction. Oxidative stress was modeled with hydrogen peroxide treatment, and metabolic stress by inhibition of glycolysis using 2-deoxyglucose (2-DG). Since cardiac myocytes in vivo are terminally differentiated cells that cannot be expanded to the numbers needed for these studies, two cardiac myocyte model cell lines were used: H9c2 cells, derived fetal rat heart; and HL-1 cells, derived from the hearts of mice with cardiac-specific expression of an SV40 T-antigen transgene. Based on the activities of compounds in each of these cell types in response to each of these death stimuli (4 assays), 10 scaffolds were prioritized for reorder of their powders and available analogs for “analog-by-catalog” (ABC) testing. Two scaffolds advanced through multiple rounds of analog synthesis and structure-activity studies to result in the first probe molecule ML330. ML330 protects both H9c2 and HL-1 cell lines (EC50 0.4–4.0 μM & Emax 42–99 %) from both oxidative and metabolic stress induced by hydrogen peroxide and 2-DG, respectively. A second probe ML331, was identified preferentially protects both cell lines (EC50 0.6–9.0 μM & Emax 39–74 %) from metabolic stress induced by 2-DG. Probe molecules ML330 and ML331 will be useful to map and understand the critical cell death pathways in cardiac myocytes and lead to the development of a pharmacological agent to limit heart damage during myocardial infarction in humans. The probe molecules may also find broad utility in studies to understand relationships that regulate connections between various cell death programs, such as apoptosis and necrosis. Moreover, these findings may also extend to other ischemic syndromes such as stroke.">
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<meta name="og:title" content="Cardioprotective inhibitors of reperfusion injury">
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<meta name="og:type" content="book">
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<meta name="og:description" content="An understanding of the mechanisms and pathways that mediate cardiac myocyte death is critical for the development of pharmacological therapies to limit heart damage during myocardial infarction (“heart attack”). We have completed the first unbiased cell-based screen of the MLSMR library consisting of ~360,000 compounds to identify small molecule probes that protect cardiac myocytes against oxidative and metabolic stresses, both precipitants of cell death during myocardial infarction. Oxidative stress was modeled with hydrogen peroxide treatment, and metabolic stress by inhibition of glycolysis using 2-deoxyglucose (2-DG). Since cardiac myocytes in vivo are terminally differentiated cells that cannot be expanded to the numbers needed for these studies, two cardiac myocyte model cell lines were used: H9c2 cells, derived fetal rat heart; and HL-1 cells, derived from the hearts of mice with cardiac-specific expression of an SV40 T-antigen transgene. Based on the activities of compounds in each of these cell types in response to each of these death stimuli (4 assays), 10 scaffolds were prioritized for reorder of their powders and available analogs for “analog-by-catalog” (ABC) testing. Two scaffolds advanced through multiple rounds of analog synthesis and structure-activity studies to result in the first probe molecule ML330. ML330 protects both H9c2 and HL-1 cell lines (EC50 0.4–4.0 μM & Emax 42–99 %) from both oxidative and metabolic stress induced by hydrogen peroxide and 2-DG, respectively. A second probe ML331, was identified preferentially protects both cell lines (EC50 0.6–9.0 μM & Emax 39–74 %) from metabolic stress induced by 2-DG. Probe molecules ML330 and ML331 will be useful to map and understand the critical cell death pathways in cardiac myocytes and lead to the development of a pharmacological agent to limit heart damage during myocardial infarction in humans. The probe molecules may also find broad utility in studies to understand relationships that regulate connections between various cell death programs, such as apoptosis and necrosis. Moreover, these findings may also extend to other ischemic syndromes such as stroke.">
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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="_NBK174883_"><span class="title" itemprop="name">Cardioprotective inhibitors of reperfusion injury</span></h1><p class="contribs">Kane A, Peddibhotla S, Maloney P, et al.</p><p class="fm-aai"><a href="#_NBK174883_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>An understanding of the mechanisms and pathways that mediate cardiac myocyte death is critical for the development of pharmacological therapies to limit heart damage during myocardial infarction (“heart attack”). We have completed the first unbiased cell-based screen of the MLSMR library consisting of ~360,000 compounds to identify small molecule probes that protect cardiac myocytes against oxidative and metabolic stresses, both precipitants of cell death during myocardial infarction. Oxidative stress was modeled with hydrogen peroxide treatment, and metabolic stress by inhibition of glycolysis using 2-deoxyglucose (2-DG). Since cardiac myocytes <i>in vivo</i> are terminally differentiated cells that cannot be expanded to the numbers needed for these studies, two cardiac myocyte model cell lines were used: H9c2 cells, derived fetal rat heart; and HL-1 cells, derived from the hearts of mice with cardiac-specific expression of an SV40 T-antigen transgene. Based on the activities of compounds in each of these cell types in response to each of these death stimuli (4 assays), 10 scaffolds were prioritized for reorder of their powders and available analogs for “analog-by-catalog” (ABC) testing. Two scaffolds advanced through multiple rounds of analog synthesis and structure-activity studies to result in the first probe molecule <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>. <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> protects both H9c2 and HL-1 cell lines (EC<sub>50</sub> 0.4–4.0 μM & E<sub>max</sub> 42–99 %) from both oxidative and metabolic stress induced by hydrogen peroxide and 2-DG, respectively. A second probe <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>, was identified preferentially protects both cell lines (EC<sub>50</sub> 0.6–9.0 μM & E<sub>max</sub> 39–74 %) from metabolic stress induced by 2-DG. Probe molecules <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> will be useful to map and understand the critical cell death pathways in cardiac myocytes and lead to the development of a pharmacological agent to limit heart damage during myocardial infarction in humans. The probe molecules may also find broad utility in studies to understand relationships that regulate connections between various cell death programs, such as apoptosis and necrosis. Moreover, these findings may also extend to other ischemic syndromes such as stroke.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 DA031671-01</p><p><b>Screening Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Chemistry Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Assay Submitter & Institution:</b> Richard N. Kitsis, Albert Einstein College of Medicine of Yeshiva University, USA.</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588508" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588508</a></p><div id="ml331.s1"><h2 id="_ml331_s1_">Probe Structure & Characteristics</h2><div id="ml331.fu1" class="figure"><div class="graphic"><img src="/books/NBK174883/bin/ml331fu1.jpg" alt="Image ml331fu1" /></div></div><p>This Center Probe Report describes two cardioprotective compounds; i) <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>, which protects H9c2 & HL-1 cells from cell-death resulting from oxidative damage caused by H<sub>2</sub>O<sub>2</sub> as well as metabolic stress imposed by 2-DG and ii) <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>, which selectively protects H9c2 and HL-1 cells from cell death resulting from metabolic stress imposed by 2-DG. Potency and selectivity characteristics for <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> are described in <a class="figpopup" href="/books/NBK174883/table/ml331.t1/?report=objectonly" target="object" rid-figpopup="figml331t1" rid-ob="figobml331t1">Table 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml331t1"><a href="/books/NBK174883/table/ml331.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml331t1" rid-ob="figobml331t1"><img class="small-thumb" src="/books/NBK174883/table/ml331.t1/?report=thumb" src-large="/books/NBK174883/table/ml331.t1/?report=previmg" alt="Table 1. Potency and selectivity characteristics for probes ML330 and ML331." /></a><div class="icnblk_cntnt"><h4 id="ml331.t1"><a href="/books/NBK174883/table/ml331.t1/?report=objectonly" target="object" rid-ob="figobml331t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Potency and selectivity characteristics for probes ML330 and ML331. </p></div></div></div><div id="ml331.s2"><h2 id="_ml331_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>There are two clear uses for the probes at present: (a) to delineate cell death pathways in cardiac myocytes that are relevant to myocardial infarction and (b) to provide a prototype for the development of a pharmacological agent to be used clinically to limit heart damage during human myocardial infarction. We note that heart damage sustained in a myocardial infarction is a primary determinant of long-term cardiac dysfunction, disability, and death. There are approximately ~50 independent labs that study cardiac myocyte death, and another ~200 that study related issues. Prior work employing genetic and pharmacological manipulations to reduce cardiac myocyte death suggest that many of these labs will use the developed probes. One set of uses will focus on understanding the complex molecular circuitry that mediates cell death in the heart – in particular, the largely undefined connections between necrosis and apoptosis. In addition, multiple labs will use the probes as a starting point to generate a drug for myocardial infarction to be used in clinical practice. This study reports one probe, <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>, which protects rat H9c2 and mouse HL-1 cardiac myocytes against both oxidative and metabolic stressors, and another probe, <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>, that protects both cell lines against metabolic stress, but not oxidative stress. These findings are informative in several respects. First, these data suggest that <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> impact different molecular targets. Second, they illustrate the species-independence of these effects, an observation that portends well for the applicability of the findings to humans.</p></div><div id="ml331.s3"><h2 id="_ml331_s3_">2. Materials and Methods</h2><p>The primary assay and secondary assays are relatively simple cytoprotection assays that read-out cell viability indirectly using a commercial cell lysis reagent, ATPLite® (PerkinElmer) to quantify the high steady-state levels of cellular ATP that healthy cells produce to drive ATP-dependent bioluminescence. <b>Cell lines:</b> Rat H9c2 cells and mouse HL-1 are two cell lines that have been used as models of cardiac myocytes. <b>Cytotoxic stressors</b>: Hydrogen peroxide simulates the oxidative stress experienced by cardiac myocytes primarily during the reperfusion phase of ischemia/reperfusion, while 2-deoxyglucose simulates the metabolic stress that occurs primarily during the ischemic phase.</p><div id="ml331.s4"><h3>2.1. Assays</h3><p>The details of the primary HTS and additional assay can be found in the “Assay Description” section in the PubChem BioAssay view under the AIDs as listed in <a class="figpopup" href="/books/NBK174883/table/ml331.t2/?report=objectonly" target="object" rid-figpopup="figml331t2" rid-ob="figobml331t2">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml331t2"><a href="/books/NBK174883/table/ml331.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml331t2" rid-ob="figobml331t2"><img class="small-thumb" src="/books/NBK174883/table/ml331.t2/?report=thumb" src-large="/books/NBK174883/table/ml331.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml331.t2"><a href="/books/NBK174883/table/ml331.t2/?report=objectonly" target="object" rid-ob="figobml331t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. Summarizes the details for the assays that drove this probe project </p></div></div></div><div id="ml331.s5"><h3>2.2. Probe Chemical Characterization</h3><p><b>Chemical name of probe compounds.</b> The IUPAC name of the probe <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> is <i>N</i>-(2-((4-acetyl-phenyl)amino)-2-oxoethyl)-6-methoxy-2-(3,4,5-trimethoxyphenyl)quinoline-4-carboxamide. The IUPAC name of <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> is 6-(2,3-dichlorobenzyl)-9,10-dimethoxy-6,6a-dihydroisoindolo[2,1-a]quin-azoline-5,11-dione. The specific batches prepared, tested and submitted to the MLSMR are archived as SID <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a>, corresponding to CID 60202221 (<a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>) and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a> corresponding to CID 60202247 (<a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>).</p><div id="ml331.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Chemical%20structures%20of%20ML330%20and%20ML331%20and%20stereochemistry%20if%20known.&p=BOOKS&id=174883_ml331f1.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/NBK174883/bin/ml331f1.jpg" alt="Figure 1. Chemical structures of ML330 and ML331 and stereochemistry if known." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Chemical structures of ML330 and ML331 and stereochemistry if known</span></h3></div><p><b>Synthesis and Structural Verification Information of probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a>, corresponding to CID 60202221 (<a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>).</b></p><div id="ml331.f8" 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%20ML330.&p=BOOKS&id=174883_ml331f8.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/NBK174883/bin/ml331f8.jpg" alt="Scheme 1. Synthesis of ML330." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML330</span></h3><div class="caption"><p>Conditions: i) KOH, ethanol, MW 100 °C, 30 minutes, 77%; ii) HATU, triethylamine, CH<sub>2</sub>Cl<sub>2</sub>, 83%; iii) CF<sub>3</sub>CO<sub>2</sub>H, CH<sub>2</sub>Cl<sub>2</sub>, 15 h, 83%; and iv) HATU, DIEA, CH<sub>2</sub>Cl<sub>2</sub>, 2 h, 67%.</p></div></div><p><b>Synthesis and Structural Verification Information of probe <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a> corresponding to CID 60202247 (<a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>).</b></p><div id="ml331.f9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK174883/bin/ml331f9.jpg" alt="Scheme 2. Synthesis of ML331." /></div><h3><span class="label">Scheme 2</span><span class="title">Synthesis of ML331</span></h3></div><div id="ml331.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%201H%20NMR%2C%2013C%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML330.&p=BOOKS&id=174883_ml331f2.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/NBK174883/bin/ml331f2.jpg" alt="Figure 2. 1H NMR, 13C NMR, and LC-MS spectra of ML330." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title"><sup>1</sup>H NMR, <sup>13</sup>C NMR, and LC-MS spectra of ML330</span></h3><div class="caption"><p>A. 1H NMR (500 MHz, DMSO-<i>d</i><sub>6</sub>). B. LC of LC-MS. C. MS of LC-MS.</p></div></div><div id="ml331.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%20and%20LC-MS%20spectra%20of%20ML331.&p=BOOKS&id=174883_ml331f3.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/NBK174883/bin/ml331f3.jpg" alt="Figure 3. 1H NMR and LC-MS spectra of ML331." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title"><sup>1</sup>H NMR and LC-MS spectra of ML331</span></h3><div class="caption"><p>A. <sup>1</sup>H NMR Spectrum of <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> (500 MHz, CDCl<sub>3</sub>). B. LC of LC-MS for <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>. (Reverse phase C18 column). C. MS of LC-MS.</p></div></div><p><b>Solubility and Stability of</b>
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<a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>
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<b>and</b>
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<a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>
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<b>in PBS at room temperature.</b> The solubility of <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> were investigated in aqueous buffers at room temperature. As noted in the <i>Summary of in vitro ADME/T properties</i>
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<a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> has low solubility in aqueous buffer at pH 5, 6.2 and 7.4 while the solubility of <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> approaches 20 μM. To evaluate their potential instability in buffer and in assay media, 1 μM solutions of <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> were prepared either in acetonitrile:PBS (1:1) or assay media which contains 400 μM hydrogen peroxide and were incubated at room temperature. The amount of the parent compounds remaining at various times were analyzed by LC/MS (<a class="figpopup" href="/books/NBK174883/figure/ml331.f4/?report=objectonly" target="object" rid-figpopup="figml331f4" rid-ob="figobml331f4">Figure 4</a>). The results indicate that both probes showed little instability in buffer and in assay media up to 24 hours, whereas prolonged exposure to the oxidative environment of the assay media led to increased decomposition of parent compounds. The stability of <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> or <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> in assay media is suitable within the time course of the primary assay (3h).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml331f4" co-legend-rid="figlgndml331f4"><a href="/books/NBK174883/figure/ml331.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml331f4" rid-ob="figobml331f4"><img class="small-thumb" src="/books/NBK174883/bin/ml331f4.gif" src-large="/books/NBK174883/bin/ml331f4.jpg" alt="Figure 4. Stability of ML330 & ML331 in Buffer." /></a><div class="icnblk_cntnt" id="figlgndml331f4"><h4 id="ml331.f4"><a href="/books/NBK174883/figure/ml331.f4/?report=objectonly" target="object" rid-ob="figobml331f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of ML330 & ML331 in Buffer. </p></div></div><p><b>MLS# verifying submission of probe molecule and five related samples submitted to the SMR collection.</b> These probes are not commercially available. Samples of the probe <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> (>25 mg), and five analogs of each (>20 mg), synthesized at SBCCG were submitted to MLSMR (<a class="figpopup" href="/books/NBK174883/table/ml331.t3/?report=objectonly" target="object" rid-figpopup="figml331t3" rid-ob="figobml331t3">Tables 3</a> and <a class="figpopup" href="/books/NBK174883/table/ml331.t4/?report=objectonly" target="object" rid-figpopup="figml331t4" rid-ob="figobml331t4">4</a>), and 5 mg of the probes were provided to the Assay Provider.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml331t3"><a href="/books/NBK174883/table/ml331.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml331t3" rid-ob="figobml331t3"><img class="small-thumb" src="/books/NBK174883/table/ml331.t3/?report=thumb" src-large="/books/NBK174883/table/ml331.t3/?report=previmg" alt="Table 3. ML330 - Probe and Analog Submissions to MLSMR (Evotec) for Cardioprotectants." /></a><div class="icnblk_cntnt"><h4 id="ml331.t3"><a href="/books/NBK174883/table/ml331.t3/?report=objectonly" target="object" rid-ob="figobml331t3">Table 3</a></h4><p class="float-caption no_bottom_margin">ML330 - Probe and Analog Submissions to MLSMR (Evotec) for <i>Cardioprotectants</i>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml331t4"><a href="/books/NBK174883/table/ml331.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml331t4" rid-ob="figobml331t4"><img class="small-thumb" src="/books/NBK174883/table/ml331.t4/?report=thumb" src-large="/books/NBK174883/table/ml331.t4/?report=previmg" alt="Table 4. ML331 - Probe and Analog Submissions to MLSMR (Evotec) for Cardioprotectants." /></a><div class="icnblk_cntnt"><h4 id="ml331.t4"><a href="/books/NBK174883/table/ml331.t4/?report=objectonly" target="object" rid-ob="figobml331t4">Table 4</a></h4><p class="float-caption no_bottom_margin">ML331 - Probe and Analog Submissions to MLSMR (Evotec) for <i>Cardioprotectants</i>. </p></div></div></div><div id="ml331.s6"><h3>2.3. Probe Preparation</h3><p><a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a>
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<b>Preparation</b>: [Pfitzinger, W. <i>J. Prakt. Chem.</i> 1886, <i>33</i>, 100.; Dasgupta, S.; Murumkar, P. R.; Giridhar, R.; Yadav, M. R. <i>Bioorg. Med. Chem.</i> 2009, <i>17</i>, 3604–3617.]</p><p>A mixture of 5-methoxyindoline-2,3-dione (1.0 g, 5.64 mmol) and KOH (1.58 g, 28.2 mmol) were weighed into a 35 mL microwave reaction vessel. Ethanol (5 mL) was added and the mixture was stirred for five minutes at 23 °C. 1-(3,4,5-trimethoxyphenyl)ethanone (1.42 g, 6.77 mmol) was added as a solid and the mixture was heated under microwave conditions at 100 °C for 0.5 h. The solvent was evaporated and residue dissolved in water (100 mL) and extracted with ethyl acetate (3x, 25 mL). The aqueous layer was acidified with conc. HCl (pH ~ 2.0) and the solution cooled at 4 °C for 15 h. The precipitate formed was collected by filtration, washed with water and air-dried to afford the product, 6-methoxy-2-(3,4,5-trimethoxyphenyl)quinoline-4-carboxylic acid (<b>A</b>) as an orange solid (1.6 g, 77%). <sup>1</sup>H NMR (500 MHz, DMSO-<i>d</i><sub>6</sub>) δ 8.46 (s, 1H), 8.09 (d, <i>J</i> = 9.2 Hz, 1H), 8.06 (d, <i>J</i> = 2.9 Hz, 1H), 7.59 – 7.43 (m, 3H), 3.93 (s, 6H), 3.92 (s, 3H), 3.75 (s, 3H). ESI-MS (+ve): calculated for C<sub>20</sub>H<sub>19</sub>NO<sub>6</sub>, [M+H] = 370.13, observed [M+H] = 370.23.</p><p>A mixture of 2-((tert-butoxycarbonyl)amino)acetic acid (400 mg, 2.28 mmol), triethylamine (0.955 mL, 6.85 mmol), and HATU (1.04 g, 2.74 mmol) in dichloromethane (12 mL) was allowed to stir 5 minutes prior to the addition of 1-(4-aminophenyl)ethanone (462 mg, 3.43 mmol). The mixture was stirred overnight and then was diluted with dichloromethane to 50 mL. The mixture was washed with water (20 mL), saturated aqueous sodium bisulfate (10 mL), water (20 mL), and saturated aqueous sodium bicarbonate (20 mL). The organic phase was dried with sodium sulfate and concentrated <i>in vacuo</i> to a yellow residue which was purified on silica gel eluting with 20–50% ethyl acetate in hexanes. The resulting Boc-protected intermediate (555 mg, 83%) was treated with 20 mL of 20% trifluoroacetic acid in dichloromethane for 2 hours. The solvent was removed <i>in vacuo</i> to provide the resulting N-(4-acetylphenyl)-2-aminoacetamide trifluoroacetic acid salt (<b>B</b>). Yield = 580 mg (83%) was used without further purification. <sup>1</sup>H NMR (500 MHz, DMSO-<i>d</i><sub>6</sub>) δ 10.92 (s, 1H), 8.26 (s, 3H), 7.98 (d, <i>J</i> = 8.7 Hz, 2H), 7.75 (d, <i>J</i> = 8.7 Hz, 2H), 3.88 (d, <i>J</i> = 12.2 Hz, 2H), 2.55 (s, 3H). ESI-MS (+ve): Calculated for C<sub>10</sub>H<sub>12</sub>N<sub>2</sub>O<sub>2</sub>, [M+H] = 193.09, observed [M+H] = 193.05.</p><p>A mixture of <b>A</b> (208 mg, 0.56 mmol), N-ethyl-N-isopropylpropan-2-amine (0.4 mL, 2.3 mmol), and HATU (235 mg, 0.62 mmol) in dichloromethane (15 mL) was allowed to stir 5 minutes prior to the addition of <b>B</b> (248 mg, 0.84 mmol). The mixture was stirred two hours and then was diluted with dichloromethane to 50 mL. The mixture was then washed with water (15mL), saturated aqueous sodium bisulfate (15mL), water (15mL), and saturated aqueous sodium bicarbonate. The organic phase was dried with sodium sulfate and the solvent was removed <i>in vacuo</i> to provide orange foam. The material was purified on silica gel eluting with 0–5% methanol in dichloromethane. Crystallization of the resulting residue from dichloromethane:hexane solution provided N-(2-((4-acetylphenyl)amino)-2-oxoethyl)-6-methoxy-2-(3,4,5-trimethoxyphenyl)quinoline-4-carboxamide as a pale yellow powder (206 mg, 67%). <sup>1</sup>H NMR (500 MHz, DMSO-<i>d</i><sub>6</sub>) δ 10.58 (s, 1H), 9.24 (t, <i>J</i> = 6.0 Hz, 1H), 8.22 (s, 1H), 8.06 (d, <i>J</i> = 9.2 Hz, 1H), 7.99 (d, <i>J</i> = 8.7 Hz, 2H), 7.93 (d, <i>J</i> = 2.8 Hz, 1H), 7.80 (d, <i>J</i> = 8.7 Hz, 2H), 7.60 (s, 2H), 7.49 (dd, <i>J</i> = 9.2, 2.8 Hz, 1H), 4.28 (d, <i>J</i> = 6.0 Hz, 2H), 3.98 (s, 3H), 3.95 (s, 6H), 3.77 (s, 4H), 2.56 (s, 3H). <sup>13</sup>C NMR (125 MHz, DMSO-<i>d</i><sub>6</sub>) δ 196.48, 168.17, 167.64, 157.66, 153.25, 152.87, 143.82, 143.23, 141.84, 138.89, 133.90, 131.78, 130.86, 129.60, 124.51, 122.55, 118.30, 116.63, 104.35, 103.90, 60.13, 56.09, 55.59, 43.18, 26.42. HRMS (ESI+ve): Calculated for C<sub>30</sub>H<sub>29</sub>N<sub>3</sub>O<sub>7</sub>, [M+H] = 544.2078, observed [M+H] = 544.2062.</p><p><a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>
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<b>Preparation:</b> [Kumar, K. S.; Kumar, P. M.; Kumar, K. A.; Sreenivasulu, M.; Jafar, A. A.; Rambabu, D.; Krishna, G. R.; Reddy, C. M.; Kapavarapu, R.; Shivakumar, K.; Priya, K. K.; Parsa, K. V. L.; Pal, M. <i>Chem. Commun</i>. 2011, <i>47</i>, 5010–12.]</p><p>Isatoic anyhydride (100 mg, 0.61 mmol), 2-carboxy-3,4-dimethoxybenzaldehyde (140 mg, 0.66 mmol), and 2,3-dichlorobenzylamine (116 mg, 0.66 mmol), montmorillonite K-10 (5%, 100 mg) and isopropanol (1.2 mL) were combined in a reaction tube and heated under microwave conditions at 150 °C for 2 h. The semisolid mixture was filtered with assistance from about 10 mL of chloroform. The filtrate was concentrated and the residue was purified via flash chromatography, using 50 mL of silica gel and eluting with 25% ethyl acetate in hexanes. The product <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> was recovered as an amorphous white solid, 105.7 mg (37%). <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 8.23 (dd, <i>J</i> = 7.8, 1.5 Hz, 1H), 8.15 (dd, <i>J</i> = 8.2, 1.1 Hz, 1H), 7.78 – 7.64 (m, 1H), 7.46 – 7.33 (m, 2H), 7.11 (t, <i>J</i> = 7.9 Hz, 1H), 7.04 (d, <i>J</i> = 8.3 Hz, 1H), 7.02 – 6.88 (m, 2H), 6.29 – 6.21 (m, 1H), 5.19 (d, <i>J</i> = 17.6 Hz, 1H), 5.09 (d, <i>J</i> = 17.6 Hz, 1H), 4.10 (s, 3H), 3.91 (s, 3H); <sup>13</sup>C NMR (125 MHz, CDCl<sub>3</sub>) δ 164.13, 163.14, 154.45, 148.32, 137.11, 136.42, 133.89, 133.42, 129.74, 129.42, 129.07, 127.55, 125.39, 125.02, 120.55, 120.07, 116.54, 69.63, 62.63, 56.57, 45.09; HRMS (ESI+ve): Calculated for C<sub>24</sub>H<sub>19</sub>Cl<sub>2</sub>N<sub>2</sub>O<sub>4</sub>, [M+H] = 469.0716, observed [M+H] = 469.0690. Calculated for C<sub>24</sub>H<sub>18</sub>Cl<sub>2</sub>N<sub>2</sub>NaO<sub>4</sub>, [M+Na] = 491.0536, observed [M+Na] = 491.0536.</p><p>All reactions involving air and moisture-sensitive reagents and solvents were performed under a nitrogen atmosphere using standard chemical techniques. Anhydrous solvents were purchased and freshly used from Sigma-Aldrich or EMD Biosciences. All organic reagents were used as purchased. Analytical thin-layer chromatography was performed on Partisil K6F silica gel 60 Å, 250 μm. Microwave-assisted reactions were performed using a CEM Discover system. <sup>1</sup>H and <sup>13</sup>C chemical shifts are reported in values in ppm in the corresponding solvent. All solvents used for chromatography on the synthetic materials were Fisher Scientific HPLC grade, and the water was Millipore Milli-Q PP filtered. LCMS analysis of synthetic materials was completed on a Waters Autopurification system, which consists of a 2767 sample manager, a 2545 binary gradient module, a system fluidics organizer, a 2489 UV/vis detector, and a 3100 mass detector, all controlled with MassLynx software. A Sunfire Analytical C18 5 μm column (4.6 × 50 mm) and stepwise gradient {10% [(MeCN + 0.1% TFA) in (water + 0.1% TFA)] to 98% [(MeCN + 0.1% TFA) in (water + 0.1% TFA)] for 9 min.} was used for analytical LCMS of final compounds. The final compounds were purified by silica gel flash chromatography. All NMR spectra for the synthetic materials were recorded on a Bruker Avance II 400 or DRX-500 MHz instrument. MestReNova 7 program was used to process and interpret NMR spectra. High Resolution Mass Spectrometry (HRMS) spectra were carried out on an Agilent 6224A Accurate-Mass Time-of-Flight (TOF) LC/MS system with electron spray ionization (ESI).</p></div></div><div id="ml331.s7"><h2 id="_ml331_s7_">3. Results</h2><div id="ml331.s8"><h3>3.1. Dose Response Curves for Probe</h3><p><a class="figpopup" href="/books/NBK174883/figure/ml331.f5/?report=objectonly" target="object" rid-figpopup="figml331f5" rid-ob="figobml331f5">Figures 5A</a> and <a class="figpopup" href="/books/NBK174883/figure/ml331.f6/?report=objectonly" target="object" rid-figpopup="figml331f6" rid-ob="figobml331f6">5B</a> illuminate the matrix of dose response results for <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML332[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML332</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml331f5" co-legend-rid="figlgndml331f5"><a href="/books/NBK174883/figure/ml331.f5/?report=objectonly" target="object" title="Figure 5A" class="img_link icnblk_img figpopup" rid-figpopup="figml331f5" rid-ob="figobml331f5"><img class="small-thumb" src="/books/NBK174883/bin/ml331f5.gif" src-large="/books/NBK174883/bin/ml331f5.jpg" alt="Figure 5A. EC50 determinations from full dose-response curves tested in quadruplicate runs for ML330 in all assays." /></a><div class="icnblk_cntnt" id="figlgndml331f5"><h4 id="ml331.f5"><a href="/books/NBK174883/figure/ml331.f5/?report=objectonly" target="object" rid-ob="figobml331f5">Figure 5A</a></h4><p class="float-caption no_bottom_margin">EC<sub>50</sub> determinations from full dose-response curves tested in quadruplicate runs for ML330 in all assays. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml331f6" co-legend-rid="figlgndml331f6"><a href="/books/NBK174883/figure/ml331.f6/?report=objectonly" target="object" title="Figure 5B" class="img_link icnblk_img figpopup" rid-figpopup="figml331f6" rid-ob="figobml331f6"><img class="small-thumb" src="/books/NBK174883/bin/ml331f6.gif" src-large="/books/NBK174883/bin/ml331f6.jpg" alt="Figure 5B. EC50 determinations from full dose-response curves tested in quadruplicate runs for ML331 in all assays." /></a><div class="icnblk_cntnt" id="figlgndml331f6"><h4 id="ml331.f6"><a href="/books/NBK174883/figure/ml331.f6/?report=objectonly" target="object" rid-ob="figobml331f6">Figure 5B</a></h4><p class="float-caption no_bottom_margin">EC<sub>50</sub> determinations from full dose-response curves tested in quadruplicate runs for ML331 in all assays. </p></div></div></div><div id="ml331.s9"><h3>3.2. Cellular Activity</h3><p>Both probes, <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> are active in cells because the primary, confirmatory and secondary assays were all conducted in cell-based systems. It should also be noted that neither probe shows any significant cytotoxicity (LD<sub>50</sub>) relative to its potency (EC<sub>50</sub>) against a human hepatocyte cell line (<i>see</i><a class="figpopup" href="/books/NBK174883/table/ml331.t5/?report=objectonly" target="object" rid-figpopup="figml331t5" rid-ob="figobml331t5">Table 5</a> ADME/T properties).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml331t5"><a href="/books/NBK174883/table/ml331.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml331t5" rid-ob="figobml331t5"><img class="small-thumb" src="/books/NBK174883/table/ml331.t5/?report=thumb" src-large="/books/NBK174883/table/ml331.t5/?report=previmg" alt="Table 5. Summary of in vitro ADME/T Properties of Cardioprotectants ML330 and ML331." /></a><div class="icnblk_cntnt"><h4 id="ml331.t5"><a href="/books/NBK174883/table/ml331.t5/?report=objectonly" target="object" rid-ob="figobml331t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME/T Properties of Cardioprotectants ML330 and ML331. </p></div></div></div><div id="ml331.s10"><h3>3.3. Profiling Assays</h3><p>As a <i>pro forma</i> activity, the SBCCG is committed to profiling all final probe(s) compound(s) and in certain cases key informative analogs in the PanLabs full panel as negotiated by the MLPCN network. Additional commercial profiling services will be considered for funding by SBCCG as deemed appropriate and informative. The nominated probes were evaluated in a detailed <i>in vitro</i> pharmacology screen as shown in <a class="figpopup" href="/books/NBK174883/table/ml331.t5/?report=objectonly" target="object" rid-figpopup="figml331t5" rid-ob="figobml331t5">Table 5</a>.</p><p>While <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> demonstrates low solubility in aqueous media at pH 5.0, 6.2, and 7.4, <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> is soluble in excess of its reported IC<sub>50</sub> value at all three pH points.</p><p>The PAMPA (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <i>in vitro</i> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. Both <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> exhibit high permeability.</p><p>Plasma protein binding is a measure of a drug’s efficiency to bind to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> is highly bound to human plasma proteins yet is undetectable in the corresponding mouse study. This observation may be accounted for by the rapid degradation of <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> in mouse plasma. <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> is highly bound to both human and mouse plasma proteins.</p><p>Plasma stability is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which strongly can influence the <i>in vivo</i> efficacy of a test compound. Drug candidates are exposed in plasma to enzymatic processes (proteinases, esterases), and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. Both of the probes are relatively stable in human plasma after 3 hr; however, <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> is highly metabolized in mouse plasma whereas <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> is only modestly degraded. This is likely why <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> was undetectable in the mouse plasma protein binding assay.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> shows poor stability (3.9 % & 1.6% remaining at 60 min) in both human and mouse liver homogenates. <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> shows a similar lack of stability with 4.6 % and 0.4 % remaining, respectively. The lack of microsomal stability may be anticipated based on the presence of multiple methoxy groups in each probe. Unfortunately, in both cases the SAR demanded the presence of multiple methoxy substituents.</p><p>Both <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> show no toxicity (>50 μM) toward human hepatocytes.</p><p><b>Profiling against other GPCRs</b>. The two probes, <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> (CID 60202221) and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> (CID 60202247), were submitted to the Psychoactive Drug Screening Program (PDSP) at the University of North Carolina (Bryan Roth, PI) and the data against a GPCR binding assay panel is shown in <a class="figpopup" href="/books/NBK174883/figure/ml331.f7/?report=objectonly" target="object" rid-figpopup="figml331f7" rid-ob="figobml331f7">Figure 6</a>. Preliminary results indicate that both <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> and <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> show a low level of promiscuity (at 10 μM). It is not known whether these activities in binding assays are translated into functional modification of the activities of these receptors.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml331f7" co-legend-rid="figlgndml331f7"><a href="/books/NBK174883/figure/ml331.f7/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml331f7" rid-ob="figobml331f7"><img class="small-thumb" src="/books/NBK174883/bin/ml331f7.gif" src-large="/books/NBK174883/bin/ml331f7.jpg" alt="Figure 6. Profile of ML330 and ML331 in Psychoactive Drug Screening Program (PDSP) panel (% inhibition at 10 μM)." /></a><div class="icnblk_cntnt" id="figlgndml331f7"><h4 id="ml331.f7"><a href="/books/NBK174883/figure/ml331.f7/?report=objectonly" target="object" rid-ob="figobml331f7">Figure 6</a></h4><p class="float-caption no_bottom_margin">Profile of ML330 and ML331 in Psychoactive Drug Screening Program (PDSP) panel (% inhibition at 10 μM). </p></div></div></div></div><div id="ml331.s11"><h2 id="_ml331_s11_">4. Discussion</h2><p>Myocardial infarction (“heart attack”) is one of the most common causes of morbidity and mortality in the United States (~1 every 35 seconds in the U.S; of which ~250,000 are fatal)<sup><a class="bibr" href="#ml331.r1" rid="ml331.r1">1</a></sup>. This syndrome is precipitated by the acute rupture of an atherosclerotic plaque leading to thrombotic occlusion of a coronary artery. The sudden cessation of blood flow leads within hours to massive death of heart cardiac myocytes by apoptosis and necrosis<sup><a class="bibr" href="#ml331.r2" rid="ml331.r2">2</a></sup>. For the most severe type of myocardial infarction, prompt myocardial reperfusion (restoration of blood flow by opening up the vessel via angioplasty/stenting) is currently standard therapy<sup><a class="bibr" href="#ml331.r3" rid="ml331.r3">3</a>,<a class="bibr" href="#ml331.r4" rid="ml331.r4">4</a></sup>. While reperfusion itself can augment cell death, data in humans has established unequivocally that restoration of blood results in an overall salvage of cardiac myocytes. A major clinical issue is that reperfusion must be accomplished promptly (within the first 4–6 hours) in order to achieve optimal salvage of heart muscle.</p><p>Work over the past 25 years in lower organisms and mammals has led to the recognition that a significant portion of cell death – both apoptosis and necrosis – occurs in a deliberate and highly regulated manner<sup><a class="bibr" href="#ml331.r5" rid="ml331.r5">5</a>–<a class="bibr" href="#ml331.r8" rid="ml331.r8">8</a></sup>. Extensive genetic, biochemical, and pharmacological studies from the PI<sup><a class="bibr" href="#ml331.r2" rid="ml331.r2">2</a>,<a class="bibr" href="#ml331.r9" rid="ml331.r9">9</a>–<a class="bibr" href="#ml331.r27" rid="ml331.r27">27</a></sup> and others have delineated multiple mechanisms that mediate cell death in the heart. Importantly, this work has shown that cardiac myocyte death during myocardial infarction can be inhibited, resulting in the reduction of infarct size and preservation of cardiac function<sup><a class="bibr" href="#ml331.r2" rid="ml331.r2">2</a></sup>. Taken together, this research suggests the possibility that inhibition of the cell death process itself may provide a novel approach to limiting heart muscle damage during myocardial infarction.</p><p>In addition to their medical uses, the developed probes will aid research efforts to understand apoptotic and necrotic death programs in the heart.<sup><a class="bibr" href="#ml331.r2" rid="ml331.r2">2</a>,<a class="bibr" href="#ml331.r28" rid="ml331.r28">28</a></sup> Future work will delineate which death pathway(s) are impacted by these molecules and, ultimately, identify the cellular targets against which these drugs are directed.</p><div id="ml331.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Additional recent SciFinder searches by our Center Chemists for prior art found several cardioprotective agents. These blockers of cell death were developed against specific targets in death pathways. These include caspase inhibitors<sup><a class="bibr" href="#ml331.r29" rid="ml331.r29">29</a>–<a class="bibr" href="#ml331.r32" rid="ml331.r32">32</a></sup>, UCF-101<sup><a class="bibr" href="#ml331.r33" rid="ml331.r33">33</a>,<a class="bibr" href="#ml331.r34" rid="ml331.r34">34</a></sup> (which inhibits the serine protease activity of Omi/HtrA2), and necrostatin-1<sup><a class="bibr" href="#ml331.r35" rid="ml331.r35">35</a>–<a class="bibr" href="#ml331.r37" rid="ml331.r37">37</a></sup> (which inhibits the serine-threonine kinase activity of RIP1). However, the clinical suitability of these compounds and whether they are directed against the optimal cellular targets remains untested.</p><p>In 2007, Modis<sup><a class="bibr" href="#ml331.r38" rid="ml331.r38">38</a></sup> reported on a number of related dopamine D1 receptor agonists found from testing of the commercially available Sigma LOPAC<sup>®</sup> (<u>L</u>ibrary <u>o</u>f <u>P</u>haracologically <u>A</u>ctive <u>C</u>ompounds) collection based on the parent 7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compound (APB) provided significant cytoprotection at 3 h, but only the chloro- and bromo-APB and chloro-PB hydrobromide showed a similar effect at 24 h. Full-dose analysis and IC<sub>50</sub> determinations of these were not reported, however, in this study, chloro-APB was 40% cytoprotective against H<sub>2</sub>O<sub>2</sub> challenge at 30 μM, suggesting that the potency of these APBs are in the range of 50–100 μM for cytoprotection. PubChem has two entries for this parent compound CID 1225 (racemate) and CID 6603757 (<i>S</i>-enantiomer) and the details therein provide hyperlinks to some commercial sources. Neither compound appears to be available directly or has been deposited in the MLSMR, and neither compound has been reported to be active in cytoprotection.</p><div id="ml331.fu2" class="figure"><div class="graphic"><img src="/books/NBK174883/bin/ml331fu2.jpg" alt="Image ml331fu2" /></div></div><p>The probes identified herein are potent and efficacious small molecule probes that represent novel scaffolds, and are the first-in-class examples of probes provided to the research community for cardioprotection that have be deposited to the MLSMR, through an unbiased screen. These new probes will be useful in two respects: (a) as tools to further interrogate death pathways in the heart and (b) as prototypes for potential drug development. Currently there are no drugs directed specifically at inhibiting cell death in heart disease for which efficacy has been demonstrated. Thus, although other targets (e.g. caspase inhibitors) have been considered, there is no existing art with which to compare the probes identified in the current studies.</p><p>Accordingly, if validated in subsequent cell culture and whole animal experiments, these probes will function as prototypes for the development of potential drugs to reduce infarct size during human myocardial infarction. The most likely clinical possibility is that these drugs would be used in conjunction with reperfusion therapy (e.g. acute angioplasty/stenting), so as to promote cardiomyocyte rescue through complementary mechanisms of restoring the availability of oxygen and nutrients and impeding intrinsic cell suicide mechanisms. A particularly attractive possibility is that such drugs may sufficiently slow the kinetics of cell death so as to extend the time window in which reperfusuion therapy would be effective.</p></div></div><div id="ml331.s13"><h2 id="_ml331_s13_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml331.r1">Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A, Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T, Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J. Heart disease and stroke statistics--2010 update: a report from the American Heart Association. <span><span class="ref-journal">Circulation. </span><span class="ref-vol">121</span>(7):e46–e215.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20019324" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20019324</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml331.r2">Whelan RS, Kaplinskiy V, Kitsis RN. Cell death in the pathogenesis of heart disease: mechanisms and significance. <span><span class="ref-journal">Annu. Rev. Physiol. </span>2010;<span class="ref-vol">72</span></span> (in press) [<a href="https://pubmed.ncbi.nlm.nih.gov/20148665" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20148665</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml331.r3">Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. <span><span class="ref-journal">Lancet. </span>2003;<span class="ref-vol">361</span>(9351):13–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12517460" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12517460</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml331.r4">Terkelsen CJ, Christiansen EH, Sorensen JT, Kristensen SD, Lassen JF, Thuesen L, Andersen HR, Vach W, Nielsen TT. Primary PCI as the preferred reperfusion therapy in STEMI: it is a matter of time. <span><span class="ref-journal">Heart. </span>2009;<span class="ref-vol">95</span>(5):362–369.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19218262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19218262</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml331.r5">Danial NN, Korsmeyer SJ. Cell death: critical control points. <span><span class="ref-journal">Cell. </span>2004;<span class="ref-vol">116</span>(2):205–219.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14744432" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14744432</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml331.r6">Nakagawa T, Shimizu S, Watanabe T, Yamaguchi O, Otsu K, Yamagata H, Inohara H, Kubo T, Tsujimoto Y. Cyclophilin D-dependent mitochondrial permeability transition regulates some necrotic but not apoptotic cell death. <span><span class="ref-journal">Nature. </span>2005;<span class="ref-vol">434</span>(7033):652–658.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15800626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15800626</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml331.r7">Baines CP, Kaiser RA, Purcell NH, Blair NS, Osinska H, Hambleton MA, Brunskill EW, Sayen MR, Gottlieb RA, Dorn GW, Robbins J, Molkentin JD. Loss of cyclophilin D reveals a critical role for mitochondrial permeability transition in cell death. <span><span class="ref-journal">Nature. </span>2005;<span class="ref-vol">434</span>(7033):658–662.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15800627" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15800627</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml331.r8">Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2005;<span class="ref-vol">102</span>(34):12005–12010.</span> [<a href="/pmc/articles/PMC1189333/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1189333</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16103352" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16103352</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml331.r9">Bialik S, Geenen DL, Sasson IE, Cheng R, Horner JW, Evans SM, Lord EM, Koch CJ, Kitsis RN. Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. <span><span class="ref-journal">J Clin Invest. </span>1997;<span class="ref-vol">100</span>(6):1363–1372.</span> [<a href="/pmc/articles/PMC508314/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC508314</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/9294101" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9294101</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml331.r10">Shizukuda Y, Buttrick PM, Geenen DL, Borczuk AC, Kitsis RN, Sonnenblick EH. beta-adrenergic stimulation causes cardiocyte apoptosis: influence of tachycardia and hypertrophy. <span><span class="ref-journal">Am J Physiol. </span>1998;<span class="ref-vol">275</span>(3 Pt 2):H961–968.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9724301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9724301</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml331.r11">Bialik S, Cryns VL, Drincic A, Miyata S, Wollowick AL, Srinivasan A, Kitsis RN. The mitochondrial apoptotic pathway is activated by serum and glucose deprivation in cardiac myocytes. <span><span class="ref-journal">Circ Res. </span>1999;<span class="ref-vol">85</span>(5):403–414.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10473670" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10473670</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml331.r12">Fujio Y, Nguyen T, Wencker D, Kitsis RN, Walsh K. Akt promotes survival of cardiomyocytes <em>in vitro</em> and protects against ischemia-reperfusion injury in mouse heart. <span><span class="ref-journal">Circulation. </span>2000;<span class="ref-vol">101</span>(6):660–667.</span> [<a href="/pmc/articles/PMC3627349/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3627349</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10673259" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10673259</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml331.r13">Miao W, Luo Z, Kitsis RN, Walsh K. Intracoronary, adenovirus-mediated Akt gene transfer in heart limits infarct size following ischemia-reperfusion injury <em>in vivo</em>. <span><span class="ref-journal">J Mol Cell Cardiol. </span>2000;<span class="ref-vol">32</span>(12):2397–2402.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11113015" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11113015</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml331.r14">Gottlieb RA, Kitsis RN. Seeing death in the living. <span><span class="ref-journal">Nat Med. </span>2001;<span class="ref-vol">7</span>(12):1277–1278.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11726959" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11726959</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml331.r15">Lee P, Sata M, Lefer DJ, Factor SM, Walsh K, Kitsis RN. Fas pathway is a critical mediator of cardiac myocyte death and MI during ischemia-reperfusion <em>in vivo</em>. <span><span class="ref-journal">Am J Physiol Heart Circ Physiol. </span>2003;<span class="ref-vol">284</span>(2):H456–463.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12414449" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12414449</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml331.r16">Wencker D, Chandra M, Nguyen K, Miao W, Garantziotis S, Factor SM, Shirani J, Armstrong RC, Kitsis RN. A mechanistic role for cardiac myocyte apoptosis in heart failure. <span><span class="ref-journal">J Clin Invest. </span>2003;<span class="ref-vol">111</span>(10):1497–1504.</span> [<a href="/pmc/articles/PMC155051/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC155051</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12750399" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12750399</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml331.r17">Tarzami ST, Miao W, Mani K, Lopez L, Factor SM, Berman JW, Kitsis RN. Opposing effects mediated by the chemokine receptor CXCR2 on myocardial ischemia-reperfusion injury: recruitment of potentially damaging neutrophils and direct myocardial protection. <span><span class="ref-journal">Circulation. </span>2003;<span class="ref-vol">108</span>(19):2387–2392.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14568904" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14568904</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml331.r18">Hayakawa Y, Chandra M, Miao W, Shirani J, Brown JH, Dorn GW 2nd, Armstrong RC, Kitsis RN. Inhibition of cardiac myocyte apoptosis improves cardiac function and abolishes mortality in the peripartum cardiomyopathy of Galpha(q) transgenic mice. <span><span class="ref-journal">Circulation. </span>2003;<span class="ref-vol">108</span>(24):3036–3041.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14638549" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14638549</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml331.r19">Nam YJ, Mani K, Ashton AW, Peng CF, Krishnamurthy B, Hayakawa Y, Lee P, Korsmeyer SJ, Kitsis RN. Inhibition of both the extrinsic and intrinsic death pathways through nonhomotypic death-fold interactions. <span><span class="ref-journal">Mol Cell. </span>2004;<span class="ref-vol">15</span>(6):901–912.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15383280" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15383280</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml331.r20">Crow MT, Mani K, Nam YJ, Kitsis RN. The mitochondrial death pathway and cardiac myocyte apoptosis. <span><span class="ref-journal">Circ Res. </span>2004;<span class="ref-vol">95</span>(10):957–970.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15539639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15539639</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml331.r21">Foo RS, Mani K, Kitsis RN. Death begets failure in the heart. <span><span class="ref-journal">J Clin Invest. </span>2005;<span class="ref-vol">115</span>(3):565–571.</span> [<a href="/pmc/articles/PMC1052022/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1052022</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15765138" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15765138</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml331.r22">Kitsis RN, Jialal I. Limiting myocardial damage during acute myocardial infarction by inhibiting Creactive protein. <span><span class="ref-journal">N Engl J Med. </span>2006;<span class="ref-vol">355</span>(5):513–515.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16885557" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16885557</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml331.r23">Nam YJ, Mani K, Wu L, Peng CF, Calvert JW, Foo RS, Krishnamurthy B, Miao W, Ashton AW, Lefer DJ, Kitsis RN. The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant. <span><span class="ref-journal">J Biol Chem. </span>2007;<span class="ref-vol">282</span>(8):5522–5528.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17142452" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17142452</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml331.r24">Foo RS, Chan LK, Kitsis RN, Bennett MR. Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. <span><span class="ref-journal">J Biol Chem. </span>2007;<span class="ref-vol">282</span>(8):5529–5535.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17142834" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17142834</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml331.r25">Kitsis RN, Peng CF, Cuervo AM. Eat your heart out. <span><span class="ref-journal">Nat Med. </span>2007;<span class="ref-vol">13</span>(5):539–541.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17479097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17479097</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml331.r26">Whelan RS, Mani K, Kitsis RN. Nipping at cardiac remodeling. <span><span class="ref-journal">J Clin Invest. </span>2007;<span class="ref-vol">117</span>(10):2751–2753.</span> [<a href="/pmc/articles/PMC1994642/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1994642</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17909620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17909620</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml331.r27">Foo RS, Nam YJ, Ostreicher MJ, Metzl MD, Whelan RS, Peng CF, Ashton AW, Fu W, Mani K, Chin SF, Provenzano E, Ellis I, Figg N, Pinder S, Bennett MR, Caldas C, Kitsis RN. Regulation of p53 tetramerization and nuclear export by ARC. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2007;<span class="ref-vol">104</span>(52):20826–20831.</span> [<a href="/pmc/articles/PMC2409226/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2409226</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18087040" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18087040</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml331.r28">Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nunez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. <span><span class="ref-journal">Cell Death Differ. </span>2009;<span class="ref-vol">16</span>(1):3–11.</span> [<a href="/pmc/articles/PMC2744427/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2744427</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18846107" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18846107</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="ml331.r29">Holly TA, Drincic A, Byun Y, Nakamura S, Harris K, Klocke FJ, Cryns VL. Caspase inhibition reduces myocyte cell death induced by myocardial ischemia and reperfusion <em>in vivo</em>. <span><span class="ref-journal">J Mol Cell Cardiol. </span>1999;<span class="ref-vol">31</span>(9):1709–1715.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10471354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10471354</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="ml331.r30">Yaoita H, Ogawa K, Maehara K, Maruyama Y. Attenuation of ischemia/reperfusion injury in rats by a caspase inhibitor. <span><span class="ref-journal">Circulation. </span>1998;<span class="ref-vol">97</span>(3):276–281.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9462530" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9462530</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="ml331.r31">Huang JQ, Radinovic S, Rezaiefar P, Black SC. <em>In vivo</em> myocardial infarct size reduction by a caspase inhibitor administered after the onset of ischemia. <span><span class="ref-journal">Eur J Pharmacol. </span>2000;<span class="ref-vol">402</span>(1–2):139–142.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10940367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10940367</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="ml331.r32">Yang W, Guastella J, Huang JC, Wang Y, Zhang L, Xue D, Tran M, Woodward R, Kasibhatla S, Tseng B, Drewe J, Cai SX. MX1013, a dipeptide caspase inhibitor with potent <em>in vivo</em> antiapoptotic activity. <span><span class="ref-journal">Br J Pharmacol. </span>2003;<span class="ref-vol">140</span>(2):402–412.</span> [<a href="/pmc/articles/PMC1574042/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1574042</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12970077" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12970077</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>33.</dt><dd><div class="bk_ref" id="ml331.r33">Liu HR, Gao E, Hu A, Tao L, Qu Y, Most P, Koch WJ, Christopher TA, Lopez BL, Alnemri ES, Zervos AS, Ma XL. Role of Omi/HtrA2 in apoptotic cell death after myocardial ischemia and reperfusion. <span><span class="ref-journal">Circulation. </span>2005;<span class="ref-vol">111</span>(1):90–96.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15611365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15611365</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="ml331.r34">Bhuiyan MS, Fukunaga K. Inhibition of HtrA2/Omi ameliorates heart dysfunction following ischemia/reperfusion injury in rat heart <em>in vivo</em>. <span><span class="ref-journal">Eur J Pharmacol. </span>2007;<span class="ref-vol">557</span>(2–3):168–177.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17182030" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17182030</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="ml331.r35">Smith CC, Davidson SM, Lim SY, Simpkin JC, Hothersall JS, Yellon DM. Necrostatin: a potentially novel cardioprotective agent? <span><span class="ref-journal">Cardiovasc Drugs Ther. </span>2007;<span class="ref-vol">21</span>(4):227–233.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17665295" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17665295</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>36.</dt><dd><div class="bk_ref" id="ml331.r36">Lim SY, Davidson SM, Mocanu MM, Yellon DM, Smith CC. The cardioprotective effect of necrostatin requires the cyclophilin-D component of the mitochondrial permeability transition pore. <span><span class="ref-journal">Cardiovasc Drugs Ther. </span>2007;<span class="ref-vol">21</span>(6):467–469.</span> [<a href="/pmc/articles/PMC2874660/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2874660</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17965927" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17965927</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>37.</dt><dd><div class="bk_ref" id="ml331.r37">Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. <span><span class="ref-journal">Nat Chem Biol. </span>2008;<span class="ref-vol">4</span>(5):313–321.</span> [<a href="/pmc/articles/PMC5434866/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5434866</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18408713" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18408713</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>38.</dt><dd><div class="bk_ref" id="ml331.r38">Gero D, Modis K, Nagy N, Szoleczky P, Toth ZD, Dorman G, Szabo C. Oxidant-induced cardiomyocyte injury: identification of the cytoprotective effect of a dopamine 1 receptor agonist using a cell-based high-throughput assay. <span><span class="ref-journal">Int J Mol Med. </span>2007;<span class="ref-vol">20</span>:749–761.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17912470" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17912470</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK174883_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Ada Kane</span>,<sup>1</sup> <span itemprop="author">Satyamaheshwar Peddibhotla</span>,<sup>1</sup> <span itemprop="author">Patrick Maloney</span>,<sup>1</sup> <span itemprop="author">Alka Mehta</span>,<sup>1</sup> <span itemprop="author">Becky Hood</span>,<sup>1</sup> <span itemprop="author">Eigo Suyama</span>,<sup>1</sup> <span itemprop="author">Kevin Nguyen</span>,<sup>1</sup> <span itemprop="author">Stefan Vasile</span>,<sup>1</sup> <span itemprop="author">Laurel Leavitt</span>,<sup>1</sup> <span itemprop="author">Anton Cheltsov</span>, <span itemprop="author">Sumeet Salaiwal</span>,<sup>2</sup> <span itemprop="author">Derek Stonich</span>,<sup>2</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>1</sup> <span itemprop="author">Michael Vicchiarelli</span>,<sup>1</sup> <span itemprop="author">Layton H. Smith</span>,<sup>1</sup> <span itemprop="author">Jena Diwan</span>,<sup>2</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>2</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>2</sup> <span itemprop="author">Paul Hershberger</span>,<sup>1</sup> <span itemprop="author">Siobhan Malany</span>,<sup>1</sup><sup>,*</sup> and <span itemprop="author">Richard N. Kitsis</span><sup>3</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.</div><div class="affiliation"><sup>2</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.</div><div class="affiliation"><sup>3</sup>
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Albert Einstein College of Medicine of Yeshiva University, USA.</div><div class="affiliation">
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<sup>*</sup> Corresponding author: Siobhan Malany, Ph.D.
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@ynalams" class="oemail">gro.mahnrubdrofnas@ynalams</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">December 10, 2012</span>; Last Update: <span itemprop="dateModified">March 22, 2013</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>Kane A, Peddibhotla S, Maloney P, et al. Cardioprotective inhibitors of reperfusion injury. 2012 Dec 10 [Updated 2013 Mar 22]. 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/ml332/?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/ml329/?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="figobml331fu1"><div id="ml331.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331fu1.jpg" alt="Image ml331fu1" /></div></div></article><article data-type="table-wrap" id="figobml331t1"><div id="ml331.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Potency and selectivity characteristics for probes ML330 and ML331</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK174883/table/ml331.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml331.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml331.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml331.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1° Assay</th><th id="hd_h_ml331.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml331.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2° Assay</th><th id="hd_h_ml331.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml331.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2° Assay</th><th id="hd_h_ml331.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml331.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2° Assay</th><th id="hd_h_ml331.t1_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml331.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>CID 60202221/<a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a></b></td><td headers="hd_h_ml331.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><b>H9c2 cells</b><br /><br /><b>with H</b><sub><b>2</b></sub><b>O2</b></td><td headers="hd_h_ml331.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.44 ± 0.04 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><b>HL-1 cells</b><br /><br /><b>with H2O2</b></td><td headers="hd_h_ml331.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.0 ± 0.5 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><b>H9c2 cell</b><br /><br /><b>with 2-DG</b></td><td headers="hd_h_ml331.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9 ± 0.1 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_8" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;"><b>HL-1 cells</b><br /><br /><b>with 2-DG</b></td><td headers="hd_h_ml331.t1_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.3 ± 0.1 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223395</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td></tr><tr><td headers="hd_h_ml331.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>CID 60202247/<a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a></b></td><td headers="hd_h_ml331.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.2 ± 0.1 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>79 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.6 ± 0.2 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td><td headers="hd_h_ml331.t1_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.65 ± 0.03 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144220864</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651871</a></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml331t2"><div id="ml331.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Summary of Assays and AIDs</span></h3><div class="caption"><p>Summarizes the details for the assays that drove this probe project</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK174883/table/ml331.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml331.t2_lrgtbl__"><table><thead><tr><th id="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChem BioAssay Name</th><th id="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary assay for small molecule modulators of myocardial damage</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588508" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588508</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS identification of small molecule modulators of myocardial damage</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588492" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588492</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588779" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588779</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602211" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602211</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623867" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">623867</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624458" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">624458</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in a panel assay</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651642" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651642</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage using 2-dexoy-glucose</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588780" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588780</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dose Response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage using 2-dexoy-glucose - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602210" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602210</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dose Response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage using 2-dexoy-glucose</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">623871</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage using 2-dexoy-glucose - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624454" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">624454</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in a panel assay</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651642" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651642</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Panel (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in a panel assay - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651871" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">651871</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Panel (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage in HL-1 cells using 2-dexoy-glucose</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602217" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602217</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dose-response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in HL-1 cells using 2-dexoy-glucose</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623873" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">623873</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in HL-1 cells using 2-dexoy-glucose - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624473" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">624473</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of uHTS hits for small molecule modulators of myocardial damage in HL-1 cells using Peroxide</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602215" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">602215</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose-response)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in HL-1 cells using Peroxide</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623872" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">623872</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml331.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule modulators of myocardial damage in HL-1 cells using Peroxide - Set 2</td><td headers="hd_h_ml331.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624460" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">624460</a></td><td headers="hd_h_ml331.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Antagonist</td><td headers="hd_h_ml331.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml331.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell</td><td headers="hd_h_ml331.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml331f1"><div id="ml331.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Chemical%20structures%20of%20ML330%20and%20ML331%20and%20stereochemistry%20if%20known.&p=BOOKS&id=174883_ml331f1.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/NBK174883/bin/ml331f1.jpg" alt="Figure 1. Chemical structures of ML330 and ML331 and stereochemistry if known." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Chemical structures of ML330 and ML331 and stereochemistry if known</span></h3></div></article><article data-type="fig" id="figobml331f8"><div id="ml331.f8" 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%20ML330.&p=BOOKS&id=174883_ml331f8.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/NBK174883/bin/ml331f8.jpg" alt="Scheme 1. Synthesis of ML330." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML330</span></h3><div class="caption"><p>Conditions: i) KOH, ethanol, MW 100 °C, 30 minutes, 77%; ii) HATU, triethylamine, CH<sub>2</sub>Cl<sub>2</sub>, 83%; iii) CF<sub>3</sub>CO<sub>2</sub>H, CH<sub>2</sub>Cl<sub>2</sub>, 15 h, 83%; and iv) HATU, DIEA, CH<sub>2</sub>Cl<sub>2</sub>, 2 h, 67%.</p></div></div></article><article data-type="fig" id="figobml331f9"><div id="ml331.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331f9.jpg" alt="Scheme 2. Synthesis of ML331." /></div><h3><span class="label">Scheme 2</span><span class="title">Synthesis of ML331</span></h3></div></article><article data-type="fig" id="figobml331f2"><div id="ml331.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%201H%20NMR%2C%2013C%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML330.&p=BOOKS&id=174883_ml331f2.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/NBK174883/bin/ml331f2.jpg" alt="Figure 2. 1H NMR, 13C NMR, and LC-MS spectra of ML330." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title"><sup>1</sup>H NMR, <sup>13</sup>C NMR, and LC-MS spectra of ML330</span></h3><div class="caption"><p>A. 1H NMR (500 MHz, DMSO-<i>d</i><sub>6</sub>). B. LC of LC-MS. C. MS of LC-MS.</p></div></div></article><article data-type="fig" id="figobml331f3"><div id="ml331.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%20and%20LC-MS%20spectra%20of%20ML331.&p=BOOKS&id=174883_ml331f3.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/NBK174883/bin/ml331f3.jpg" alt="Figure 3. 1H NMR and LC-MS spectra of ML331." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title"><sup>1</sup>H NMR and LC-MS spectra of ML331</span></h3><div class="caption"><p>A. <sup>1</sup>H NMR Spectrum of <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a> (500 MHz, CDCl<sub>3</sub>). B. LC of LC-MS for <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>. (Reverse phase C18 column). C. MS of LC-MS.</p></div></div></article><article data-type="fig" id="figobml331f4"><div id="ml331.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331f4.jpg" alt="Figure 4. Stability of ML330 & ML331 in Buffer." /></div><h3><span class="label">Figure 4</span><span class="title">Stability of ML330 & ML331 in Buffer</span></h3></div></article><article data-type="table-wrap" id="figobml331t3"><div id="ml331.t3" class="table"><h3><span class="label">Table 3</span><span class="title">ML330 - Probe and Analog Submissions to MLSMR (Evotec) for <i>Cardioprotectants</i></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK174883/table/ml331.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml331.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml331.t3_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a> - CID 60202221</th></tr><tr><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (SBCCG)</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or SBCCG syn)</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml331.t3_1_1_1_1" id="hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date ordered/Submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0472060</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556080</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202221</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223395" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144223395</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0471984</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556086</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202237</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/146136403" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">146136403</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0471749</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556087</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">57383929</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/136913727" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">136913727</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0471957</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556088</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202214</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220818" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144220818</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0471744</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556089</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">29217334</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/136913722" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">136913722</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0332326</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556090</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2331793</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/136913713" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">136913713</a></td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t3_1_1_1_1 hd_h_ml331.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml331t4"><div id="ml331.t4" class="table"><h3><span class="label">Table 4</span><span class="title">ML331 - Probe and Analog Submissions to MLSMR (Evotec) for <i>Cardioprotectants</i></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK174883/table/ml331.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml331.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml331.t4_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a>- CID 60202247</th></tr><tr><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (SBCCG)</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or SBCCG syn)</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml331.t4_1_1_1_1" id="hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Date ordered/Submitted</th></tr></thead><tbody><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">471994</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556079</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202247</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220864" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144220864</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">25</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">471764</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556081</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3674352</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/136913744" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">136913744</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">471873</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556082</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3740845</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220877" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144220877</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">471793</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556083</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">57383938</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/136913746" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">136913746</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">471993</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556084</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202206</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220863" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144220863</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr><tr><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">472006</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS004556085</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">60202225</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/144220876" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">144220876</a></td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SBCCG syn</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20</td><td headers="hd_h_ml331.t4_1_1_1_1 hd_h_ml331.t4_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/19/2012</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml331f5"><div id="ml331.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331f5.jpg" alt="Figure 5A. EC50 determinations from full dose-response curves tested in quadruplicate runs for ML330 in all assays." /></div><h3><span class="label">Figure 5A</span><span class="title">EC<sub>50</sub> determinations from full dose-response curves tested in quadruplicate runs for ML330 in all assays</span></h3></div></article><article data-type="fig" id="figobml331f6"><div id="ml331.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331f6.jpg" alt="Figure 5B. EC50 determinations from full dose-response curves tested in quadruplicate runs for ML331 in all assays." /></div><h3><span class="label">Figure 5B</span><span class="title">EC<sub>50</sub> determinations from full dose-response curves tested in quadruplicate runs for ML331 in all assays</span></h3></div></article><article data-type="table-wrap" id="figobml331t5"><div id="ml331.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Summary of <i>in vitro</i> ADME/T Properties of Cardioprotectants ML330 and ML331</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK174883/table/ml331.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml331.t5_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;">ADME/T Assay Panel Component</th><th id="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML330[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML330</a><br />CID 60202221</th><th id="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML331[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML331</a><br />CID 60202247</th></tr></thead><tbody><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in pION’s buffer (μg/mL) <i>[μM]</i><sup>a</sup><br />pH 5.0/6.2/7.4</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.22/0.32/0.10<br /><i>[0.41/0.59/0.18]</i></td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">9.2/10.1/8.9<br /><i>[19.7/21.6/19.0]</i></td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in 1× PBS, pH 7.4 (μg/mL) <i>[μM]</i><sup>a</sup></td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.25 <i>[0.46]</i></td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">7.5 <i>[16.0]</i></td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>PAMPA Permeability</b>, P<sub>e</sub> (×10<sup>−6</sup> cm/s)<br />Donor pH: 5.0/6.2/7.4 Acceptor pH: 7.4</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">106/107/237</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">470/409/114</td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Protein Binding</b> (% Bound)</td><td headers="hd_h_ml331.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human 1 μM/10 μM</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.58/99.37</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.47/99.41</td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Mouse 1 μM/10 μM</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.16/99.14</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Stability</b> (%Remaining at 3 hrs) Human/Mouse</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">96.4/0.05</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">80.03/71.91</td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Hepatic Microsome Stability</b> (% Remaining at 1hr) Human/Mouse</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.91/1.56</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.60/0.24</td></tr><tr><td headers="hd_h_ml331.t5_1_1_1_1" colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Toxicity</b> Towards Fa2N-4 Immortalized Human Hepatocytes LC<sub>50</sub> (μM)</td><td headers="hd_h_ml331.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50</td><td headers="hd_h_ml331.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>50</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="ml331.tfn1"><p class="no_margin">Solubility also expressed in molar units (μM) as indicated in <i>italicized [bracketed values],</i> in addition to more traditional μg/mL units.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml331f7"><div id="ml331.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%206.%20Profile%20of%20ML330%20and%20ML331%20in%20Psychoactive%20Drug%20Screening%20Program%20(PDSP)%20panel%20(%25%20inhibition%20at%2010%20%003BCM).&p=BOOKS&id=174883_ml331f7.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/NBK174883/bin/ml331f7.jpg" alt="Figure 6. Profile of ML330 and ML331 in Psychoactive Drug Screening Program (PDSP) panel (% inhibition at 10 μM)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 6</span><span class="title">Profile of ML330 and ML331 in Psychoactive Drug Screening Program (PDSP) panel (% inhibition at 10 μM)</span></h3></div></article><article data-type="fig" id="figobml331fu2"><div id="ml331.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK174883/bin/ml331fu2.jpg" alt="Image ml331fu2" /></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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