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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>A Selective Murine Intestinal Alkaline Phosphatase (muIAP) Inhibitor - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_title" content="A Selective Murine Intestinal Alkaline Phosphatase (muIAP) Inhibitor">
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<meta name="citation_date" content="2013/03/07">
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<meta name="citation_author" content="Stefan Vasile">
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<meta name="citation_author" content="Eduard Sergienko">
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<meta name="citation_author" content="Shenghua Shi">
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<meta name="citation_author" content="Sylvia Kim">
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<meta name="citation_author" content="Hung Nguyen">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Fu-Yue Zeng">
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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="Jonathan Kaunitz">
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<meta name="citation_author" content="José Luis Millán">
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<meta name="citation_pmid" content="23762953">
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<meta name="DC.Title" content="A Selective Murine Intestinal Alkaline Phosphatase (muIAP) Inhibitor">
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<meta name="DC.Contributor" content="Santhi Ganji">
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<meta name="DC.Contributor" content="Jiwen Zou">
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<meta name="DC.Contributor" content="Brock Brown">
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<meta name="DC.Contributor" content="Ekaterina V. Bobkova">
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<meta name="DC.Contributor" content="Robert Ardecky">
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<meta name="DC.Contributor" content="Craig Rosenstein">
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<meta name="DC.Contributor" content="Ian Pass">
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<meta name="DC.Contributor" content="Russell Dahl">
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<meta name="DC.Contributor" content="Stefan Vasile">
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<meta name="DC.Contributor" content="Eduard Sergienko">
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<meta name="DC.Contributor" content="Shenghua Shi">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Anton Cheltov">
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<meta name="DC.Contributor" content="Ying Su">
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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="Danielle McAnally">
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<meta name="DC.Contributor" content="Sylvia Kim">
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<meta name="DC.Contributor" content="Hung Nguyen">
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<meta name="DC.Contributor" content="Tina Kiffer Moreira">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Fu-Yue Zeng">
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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="Jonathan Kaunitz">
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<meta name="DC.Contributor" content="José Luis Millán">
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<meta name="description" content="The isozymes of alkaline phosphatase (AP) are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. Their localization in proximity to the cell surface suggests that they help facilitate the movement of substances across the plasma membrane. In humans, four isozymes of APs have been identified - one tissue-nonspecific (TNAP) and three tissue-specific isozymes named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) alkaline phosphatases.">
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<meta name="og:description" content="The isozymes of alkaline phosphatase (AP) are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. Their localization in proximity to the cell surface suggests that they help facilitate the movement of substances across the plasma membrane. In humans, four isozymes of APs have been identified - one tissue-nonspecific (TNAP) and three tissue-specific isozymes named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) alkaline phosphatases.">
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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="_NBK143562_"><span class="title" itemprop="name">A Selective Murine Intestinal Alkaline Phosphatase (muIAP) Inhibitor</span></h1><p class="contribs">Ganji S, Zou J, Brown B, et al.</p><p class="fm-aai"><a href="#_NBK143562_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>The isozymes of alkaline phosphatase (AP) are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates <i>in vitro</i>. Their localization in proximity to the cell surface suggests that they help facilitate the movement of substances across the plasma membrane. In humans, four isozymes of APs have been identified - one tissue-nonspecific (TNAP) and three tissue-specific isozymes named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) alkaline phosphatases.</p><p>This project sought to identify isozyme and species selective inhibitors and activators of the human and mouse alkaline phosphatases. Concurrent high throughput screening (HTS) campaigns of the NIH Molecular Libraries Small Molecule Repository (MLSMR) library comprising ~355,000 compounds were completed against murine IAP (muIAP), human IAP (huIAP), TNAP and PLAP (<i>TNAP & PLAP are only found in humans</i>) were completed. This Center Probe Report describes the screens and structure activity relationship (SAR) elucidation that led to identification of a potent (540 nM IC<sub>50</sub>) inhibitor of the murine IAP (muIAP), with 65-fold selectivity against TNAP and >185-fold selectivity against PLAP as well as the human isoform of IAP (huIAP).</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> X01-MH077602-01</p><p><b>Screening Center Name & PI:</b> Sanford-Burnham Medical Research Institute & John C. Reed, M.D., Ph.D.</p><p><b>Chemistry Center Name & PI:</b> Sanford-Burnham Medical Research Institute & John C. Reed, M.D., Ph.D.</p><p><b>Assay Submitter & Institution:</b> Sanford-Burnham Medical Research Institute & José Luis Millán (PI)</p><p>University of California, Los Angeles, School of Medicine & Jonathan Kaunitz (co-PI)</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2818" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2818</a></p><div id="ml260.s1"><h2 id="_ml260_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes a selective and murine species-specific intestinal alkaline phosphatase (muIAP) inhibitor probe <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a>. Potency and selectivity characteristics are summarized for this probe in <a class="figpopup" href="/books/NBK143562/table/ml260.t1/?report=objectonly" target="object" rid-figpopup="figml260t1" rid-ob="figobml260t1">Table 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml260t1"><a href="/books/NBK143562/table/ml260.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml260t1" rid-ob="figobml260t1"><img class="small-thumb" src="/books/NBK143562/table/ml260.t1/?report=thumb" src-large="/books/NBK143562/table/ml260.t1/?report=previmg" alt="Table 1. Biological activity summary & AIDs for Probes." /></a><div class="icnblk_cntnt"><h4 id="ml260.t1"><a href="/books/NBK143562/table/ml260.t1/?report=objectonly" target="object" rid-ob="figobml260t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Biological activity summary & AIDs for Probes. </p></div></div><div id="ml260.fu1" class="figure"><div class="graphic"><img src="/books/NBK143562/bin/ml260fu1.jpg" alt="Image ml260fu1" /></div></div></div><div id="ml260.s2"><h2 id="_ml260_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>To the present date, the scientific research community has no good selective inhibitors of mouse intestinal alkaline phosphatase (muIAP) that discriminate between the activity of the tissue-specific isozymes of AP, murine, or human in origin, such as the mouse embryonic AP, product of the Akp5 gene and global intestinal AP, product of the Akp6 locus, or the human Placental AP (PLAP) and germ cell AP (GCAP)), to assist in elucidating its functional and physiological roles. Such roles include detoxifying bacterial endotoxins and thereby acting in the establishment of gut mucosal tolerance towards the microbiota, functioning as a rate-determining step in the absorption of fatty acids, and in the regulation of duodenal surface pH and ATP concentration. This probe can be applied to the analysis of physiologic role of IAPs and other isozymes in the gut in mouse models and in the examination of the many other hydrolytic enzymes relating to ATP release mechanisms, which are otherwise obscured by the rapid hydrolysis of ATP at the cell surface. In fact, given that the mouse <i>Akp3</i> (muIAP), <i>Akp5,</i> and <i>Akp6</i> genes are syntenic and very close together in the chromosome, obtaining double knock-out (KO) mice (e.g. <i>Akp3/Akp6</i> double KO, or <i>Akp3/Akp5</i> double KOs) to investigate function is next to impossible. So, the ability to inhibit <i>Akp3</i> (muIAP) through a chemical probe in an Akp5 or Akp6 KO mouse models will help us dissect the distinct functions of these isozymes.</p><p>The somewhat unexpected species selectivity of <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> indeed provides a tool to elucidate the molecular interactions and structural determinants of selective inhibition in the purified enzymes.</p><p>It can also be applied to the study of the basic biology of plasma membrane fatty acid uptake and the biology of pulmonary inflammation induced by pathogens. It is hoped that scientists interested in the basic biology of human AP and those interested in translational applications of that research, such as gastrointestinal and pulmonary physiologists with interests in obesity, intestinal lipid uptake, and cystic fibrosis, will find this probe of interest.</p></div><div id="ml260.s3"><h2 id="_ml260_s3_">2. Materials and Methods</h2><div id="ml260.s4"><h3>2.1. Assays</h3><p><a class="figpopup" href="/books/NBK143562/table/ml260.t2/?report=objectonly" target="object" rid-figpopup="figml260t2" rid-ob="figobml260t2">Table 2</a> summarizes the details for the assays that drove this probe project and can be found in the “Assay Description” section under the listed AIDs in <a class="figpopup" href="/books/NBK143562/table/ml260.t2/?report=objectonly" target="object" rid-figpopup="figml260t2" rid-ob="figobml260t2">Table 2</a> as viewable in <a href="/pcassay" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PubChem Bioassays</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml260t2"><a href="/books/NBK143562/table/ml260.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml260t2" rid-ob="figobml260t2"><img class="small-thumb" src="/books/NBK143562/table/ml260.t2/?report=thumb" src-large="/books/NBK143562/table/ml260.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml260.t2"><a href="/books/NBK143562/table/ml260.t2/?report=objectonly" target="object" rid-ob="figobml260t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div></div><div id="ml260.s5"><h3>2.2. Probe Chemical Characterization</h3><div id="ml260.s6"><h4>Chemical name of probe compound & structure including stereochemistry</h4><p>The IUPAC name of the probe is <i>N</i>-(2,5-dimethylphenyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetamide. The actual batch prepared, tested, and submitted to the MLSMR is archived as <a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a> corresponding to CID 50919367. It has no chiral centers. The probe molecule is not commercially available. A 20 mg sample of <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> synthesized at SBCCG has been deposited in the MLSMR (Bio-Focus DPI) (see Probe Submission <a class="figpopup" href="/books/NBK143562/table/ml260.t3/?report=objectonly" target="object" rid-figpopup="figml260t3" rid-ob="figobml260t3">Table 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml260t3"><a href="/books/NBK143562/table/ml260.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml260t3" rid-ob="figobml260t3"><img class="small-thumb" src="/books/NBK143562/table/ml260.t3/?report=thumb" src-large="/books/NBK143562/table/ml260.t3/?report=previmg" alt="Table 3. Probe and Analog Submissions to MLSMR (BioFocus DPI) for muIAP Inhibitors." /></a><div class="icnblk_cntnt"><h4 id="ml260.t3"><a href="/books/NBK143562/table/ml260.t3/?report=objectonly" target="object" rid-ob="figobml260t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (BioFocus DPI) for muIAP Inhibitors. </p></div></div><div id="ml260.f1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143562/bin/ml260f1.jpg" alt="Figure 1. Structure of ML260." /></div><h3><span class="label">Figure 1</span><span class="title">Structure of ML260</span></h3></div><p><b>Synthetic Scheme and Structural Verification</b>. Probe <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a>
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a> corresponding to CID 50919367 was synthesized according to <a class="figpopup" href="/books/NBK143562/figure/ml260.f8/?report=objectonly" target="object" rid-figpopup="figml260f8" rid-ob="figobml260f8">Scheme 1</a>, and <a class="figpopup" href="/books/NBK143562/figure/ml260.f2/?report=objectonly" target="object" rid-figpopup="figml260f2" rid-ob="figobml260f2">Figs. 2</a> and <a class="figpopup" href="/books/NBK143562/figure/ml260.f3/?report=objectonly" target="object" rid-figpopup="figml260f3" rid-ob="figobml260f3">3</a> provide <sup>1</sup>H NMR and LC-MS structure proof, respectively.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f8" co-legend-rid="figlgndml260f8"><a href="/books/NBK143562/figure/ml260.f8/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml260f8" rid-ob="figobml260f8"><img class="small-thumb" src="/books/NBK143562/bin/ml260f8.gif" src-large="/books/NBK143562/bin/ml260f8.jpg" alt="Scheme 1. Synthesis of ML260." /></a><div class="icnblk_cntnt" id="figlgndml260f8"><h4 id="ml260.f8"><a href="/books/NBK143562/figure/ml260.f8/?report=objectonly" target="object" rid-ob="figobml260f8">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML260. conditions: <i>a</i>. dichloromethane, triethylamine, (88% yield); <i>b</i>. trifluoroacetic acid, dichloromethane, 0°C warm to RT (100% yield); <i>c</i>. EDC, HOBT, NMM, DMF, (55%) </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f2" co-legend-rid="figlgndml260f2"><a href="/books/NBK143562/figure/ml260.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml260f2" rid-ob="figobml260f2"><img class="small-thumb" src="/books/NBK143562/bin/ml260f2.gif" src-large="/books/NBK143562/bin/ml260f2.jpg" alt="Figure 2. 1H NMR Spectrum of ML260." /></a><div class="icnblk_cntnt" id="figlgndml260f2"><h4 id="ml260.f2"><a href="/books/NBK143562/figure/ml260.f2/?report=objectonly" target="object" rid-ob="figobml260f2">Figure 2</a></h4><p class="float-caption no_bottom_margin"><sup>1</sup>H NMR Spectrum of ML260. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f3" co-legend-rid="figlgndml260f3"><a href="/books/NBK143562/figure/ml260.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml260f3" rid-ob="figobml260f3"><img class="small-thumb" src="/books/NBK143562/bin/ml260f3.gif" src-large="/books/NBK143562/bin/ml260f3.jpg" alt="Figure 3. LC-MS for ML260." /></a><div class="icnblk_cntnt" id="figlgndml260f3"><h4 id="ml260.f3"><a href="/books/NBK143562/figure/ml260.f3/?report=objectonly" target="object" rid-ob="figobml260f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">LC-MS for ML260. (Reverse phase C18 column: isocratic) </p></div></div></div><div id="ml260.s7"><h4>Solubility and Stability of probe in PBS at room temperature</h4><p>The stability and solubility of <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> was investigated in phosphate-buffered saline (PBS) at room temperature (<a class="figpopup" href="/books/NBK143562/figure/ml260.f4/?report=objectonly" target="object" rid-figpopup="figml260f4" rid-ob="figobml260f4">Figure 4</a>). A comparison of the %parent compound remaining at various times indicates that the compound is very stable for much more than 48 hrs.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f4" co-legend-rid="figlgndml260f4"><a href="/books/NBK143562/figure/ml260.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml260f4" rid-ob="figobml260f4"><img class="small-thumb" src="/books/NBK143562/bin/ml260f4.gif" src-large="/books/NBK143562/bin/ml260f4.jpg" alt="Figure 4. Stability of ML260 in 1:1 acetonitrile:PBS at room temperature." /></a><div class="icnblk_cntnt" id="figlgndml260f4"><h4 id="ml260.f4"><a href="/books/NBK143562/figure/ml260.f4/?report=objectonly" target="object" rid-ob="figobml260f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of ML260 in 1:1 acetonitrile:PBS at room temperature. </p></div></div></div><div id="ml260.s8"><h4>MLS# that were submitted to the SMR collection</h4><p>Samples of the probe and five analogs synthesized at SBCCG were submitted to MLSMR (<a class="figpopup" href="/books/NBK143562/table/ml260.t3/?report=objectonly" target="object" rid-figpopup="figml260t3" rid-ob="figobml260t3">Table 3</a>).</p></div></div><div id="ml260.s9"><h3>2.3. Probe Preparation</h3><p>(compound numbering according to <a class="figpopup" href="/books/NBK143562/figure/ml260.f8/?report=objectonly" target="object" rid-figpopup="figml260f8" rid-ob="figobml260f8">Scheme 1</a>)</p><div id="ml260.s10"><h4>Preparation of tert-butyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetate</h4><div id="ml260.fu2" class="figure"><div class="graphic"><img src="/books/NBK143562/bin/ml260fu2.jpg" alt="Image ml260fu2" /></div></div><p>2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonyl chloride <b>1</b> (2.33 g, 0.01 mol) was dissolved in 50 mL of methylene chloride containing 1 mL of triethylamine. The solution was cooled to 0°C in an ice bath and a solution of tert-butyl 2-aminoacetate (1.31 g, 0.01 mol) in 20 mL of methylene chloride was slowly added. The reaction was warmed to room temperature and when the reaction was determined to be complete by TLC, approximately 1-hour, the reaction mixture was poured into 100 mL of water, washed successively 100 mL of saturated sodium bicarbonate, 100 mL of brine, and the resultant organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel and eluted with methylene chloride to yield 2.90 g of compound <b>2</b> (88 % yield), MS ESI <i>m/z</i> 329 [M+H].</p></div><div id="ml260.s11"><h4>Preparation of 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetic acid</h4><div id="ml260.fu3" class="figure"><div class="graphic"><img src="/books/NBK143562/bin/ml260fu3.jpg" alt="Image ml260fu3" /></div></div><p>Tert-butyl 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetate <b>2</b> (2.90g, 8.8 mmol) was dissolved in 100 mL of methylene chloride and the solution was cooled to 0°C in an ice bath. At his point 10 mL of trifluoracetic acid was added and the reaction was allowed to warm to room temperature. When the reaction was determined to be complete by TLC, approximately 2-hours, the solvent was removed under reduced pressure. At this point, 50 mL of toluene and 50 mL of methylene chloride was added to the crude reaction mixture and the solvent was removed under reduced pressure. This procedure was repeated two more times and the flask was put under high vacuum for 30 minutes. The grey solid 2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetic acid <b>3</b> (2.4 g, 100 %) was not purified further and was used as isolated in the next step. MS ESI <i>m/z</i> 273 [M+H].</p></div><div id="ml260.s12"><h4>Preparation of <i>N</i>-(2,5-dimethylphenyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido) acet-amide</h4><div id="ml260.fu4" class="figure"><div class="graphic"><img src="/books/NBK143562/bin/ml260fu4.jpg" alt="Image ml260fu4" /></div></div><p>2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetic acid <b>3</b> (0.27 g, 1 mmol) was dissolved in 3 mL of dimethylformamide and EDC (0.21g, 1.1 mol), HOBT (0.17g, 1.1 mmol) and 0.5 mL of NMM was added to the solution. The reaction mixture was stirred for 30 minutes at room temperature and then a solution of 2,5-dimethylaniline <b>4</b> (0.24g 2 mmol) in 1 mL of dimethylformamide was added. The reaction was stirred overnight at room temperature and then the solvent was removed under reduced pressure. The residue was dissolved in 30 mL of ethyl acetate and the organic layer was poured into 100 mL of water, washed successively 50 mL of saturated sodium bicarbonate, 50 mL of 1 N HCl, 50 mL of brine, and the resultant organic phase was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting solid was chromatographed on silica gel and eluted with methylene chloride: ethyl acetate using a gradient of 100:1 to 90:10, to yield N-(2,5-dimethylphenyl)-2-(2-oxo-2,3-dihydrobenzo[d]oxazole-6-sulfonamido)acetamide <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> (0.20 g, 55 % yield), <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 9.18 (s, 1H), 8.08 (b, 1H), 7.71 (s, 1H), 7.67 (d, J = 6.7 Hz, 1H), 7.24 (d, J = 6.7 Hz, 1 H), 7.05 (d, J = 6.7 Hz, 1H), 6.98 (S, 1H), 6.84 (d, J = 6.7 Hz, 1H),3.66 (s, 2H), 2.49 (s, 3H), 2.19 (s, 3H), MS ESI <i>m/z</i> 376 [M+H].</p></div></div></div><div id="ml260.s13"><h2 id="_ml260_s13_">3. Results</h2><div id="ml260.s14"><h3>3.1. Dose Response Curves for Probe</h3><p>The multiple dose response titrations in <a class="figpopup" href="/books/NBK143562/figure/ml260.f5/?report=objectonly" target="object" rid-figpopup="figml260f5" rid-ob="figobml260f5">Figure 5</a> (on the right) of the probe <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> against muIAP, TNAP and PLAP highlight the 65-fold selectivity of it against TNAP and the more than 185-fold selectivity against PLAP.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f5" co-legend-rid="figlgndml260f5"><a href="/books/NBK143562/figure/ml260.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml260f5" rid-ob="figobml260f5"><img class="small-thumb" src="/books/NBK143562/bin/ml260f5.gif" src-large="/books/NBK143562/bin/ml260f5.jpg" alt="Figure 5. Multiple dose response titrations of ML260." /></a><div class="icnblk_cntnt" id="figlgndml260f5"><h4 id="ml260.f5"><a href="/books/NBK143562/figure/ml260.f5/?report=objectonly" target="object" rid-ob="figobml260f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Multiple dose response titrations of ML260. </p></div></div></div><div id="ml260.s15"><h3>3.2. Cellular Activity</h3><p>This probe is an <i>in vitro</i> inhibitor, the assay providers’ (PI and co-PI) respective laboratories will conduct further profiling and will determine the translation of these activities in further <i>in vitro</i> then <i>in vivo</i> models.</p></div><div id="ml260.s16"><h3>3.3. Profiling Assays</h3><p>The probe was evaluated in a detailed <i>in vitro</i> pharmacology panel as shown in <a class="figpopup" href="/books/NBK143562/table/ml260.t4/?report=objectonly" target="object" rid-figpopup="figml260t4" rid-ob="figobml260t4">Table 4</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml260t4"><a href="/books/NBK143562/table/ml260.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml260t4" rid-ob="figobml260t4"><img class="small-thumb" src="/books/NBK143562/table/ml260.t4/?report=thumb" src-large="/books/NBK143562/table/ml260.t4/?report=previmg" alt="Table 4. Summary of in vitro ADME Properties of Novel Selection of muIAP Inhibitor Probe ML260." /></a><div class="icnblk_cntnt"><h4 id="ml260.t4"><a href="/books/NBK143562/table/ml260.t4/?report=objectonly" target="object" rid-ob="figobml260t4">Table 4</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME Properties of Novel Selection of muIAP Inhibitor Probe ML260. </p></div></div><p><a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> is very soluble in aqueous media at pH 5.0/6.2/7.4 at more than 400-fold higher concentration than the potency of the probe for muIAP (IC<sub>50</sub> = 540 nM) at all pH’s tested.</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. Consistent with the predicted LogP, <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> is moderately permeable in this assay.</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=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> shows high binding to plasma proteins in human plasma at 1 μM and at 10 μM concentration. We were unable to determine a value for protein binding in mouse plasma, since the apparent amount of <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> in the plasma chamber was lower than in the reference chamber, which is consistent with its lower stability in mouse plasma.</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. <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> shows excellent stability in human and poor stability in mouse plasma. Mouse plasma is known to contain higher levels of these enzymes and additional enzymes, which may account for this poor stability.</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=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> shows relatively poor stability in human liver homogenates, and good stability in mouse liver homogenates that may improve the utility of this probe in <i>in vivo</i> rodent models with respect to hepatic metabolism, though this may be confounded with its apparently poor plasma stability in mice.</p></div></div><div id="ml260.s17"><h2 id="_ml260_s17_">4. Discussion</h2><p>The isozymes of alkaline phosphatase (AP; orthophosphoric monoester phosphohydrolase, EC 3.1.3.1)
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are ectoenzymes anchored onto the cytoplasmic membrane via a phosphatidylinositol glycan moiety<sup><a class="bibr" href="#ml260.r1" rid="ml260.r1">1</a>,<a class="bibr" href="#ml260.r2" rid="ml260.r2">2</a></sup>. They are
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capable of catalyzing dephosphorylation and transphosphorylation reactions of a wide spectrum of
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substrates <i>in vitro</i><a class="bibr" href="#ml260.r2" rid="ml260.r2">2</a>. These selective
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probe(s) will be useful in elucidating the functional roles of human and mouse IAPs in 1)
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detoxifying bacterial endotoxins and thereby acting in the establishment of gut mucosal tolerance towards the microbiota<sup><a class="bibr" href="#ml260.r3" rid="ml260.r3">3</a></sup>; 2) their function as a rate-limiting step in the absorption of fatty acids<sup><a class="bibr" href="#ml260.r4" rid="ml260.r4">4</a>–<a class="bibr" href="#ml260.r6" rid="ml260.r6">6</a></sup>; and 3) in its role in influencing bicarbonate secretion in the gut<sub><a class="bibr" href="#ml260.r7" rid="ml260.r7">7</a></sub>. In addition, high potency selective inhibitors of IAP isozymes would facilitate studies of ecto-purinergic regulation of duodenal bicarbonate secretion, examining the many ATP phosphohydrolases present in the intestinal brush border, which would enable the study of ATP release mechanisms<sup><a class="bibr" href="#ml260.r8" rid="ml260.r8">8</a></sup>. With respect to these latter three biological questions the role of IAP in gut biology, the most relevant selectivities towards potential “off-target” activities are for the highly expressed (and readily available) isozymes, TNAP and PLAP, As most initial studies would be in mice, we chose to drive probe development through the potency against muIAP and selectivity against huIAP, TNAP and PLAP as shown in <a class="figpopup" href="/books/NBK143562/table/ml260.t1/?report=objectonly" target="object" rid-figpopup="figml260t1" rid-ob="figobml260t1">Table 1</a>.</p><div id="ml260.s18"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>During the Molecular Library Screening Center Network (MLSCN) pilot phase or the Molecular
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Libraries Initiative (MLI), we developed a triazole probe <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a> (CID 294673, <a class="figpopup" href="/books/NBK143562/figure/ml260.f6/?report=objectonly" target="object" rid-figpopup="figml260f6" rid-ob="figobml260f6">Figure 6</a>) (<i><a href="https://mli.nih.gov/mli/?dl_id=712" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://mli.nih.gov/mli/?dl_id=712</a></i>) that was more selective for the human IAP instead of TNAP (795 nM IC<sub>50</sub>; 6.5-fold) or PLAP (4,810 nM IC<sub>50</sub>; 39-fold) and exhibited a novel mode of action: uncompetitive versus the phosphate-donor substrate. While this probe is the most potent human IAP inhibitor (122 nM in the huIAP luminescent assay) known thus far, it represents <i><u>only one</u></i> scaffold and the <i><u>species specificity</u></i> was not examined.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f6" co-legend-rid="figlgndml260f6"><a href="/books/NBK143562/figure/ml260.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml260f6" rid-ob="figobml260f6"><img class="small-thumb" src="/books/NBK143562/bin/ml260f6.gif" src-large="/books/NBK143562/bin/ml260f6.jpg" alt="Figure 6. ML038 (CID 2946732)." /></a><div class="icnblk_cntnt" id="figlgndml260f6"><h4 id="ml260.f6"><a href="/books/NBK143562/figure/ml260.f6/?report=objectonly" target="object" rid-ob="figobml260f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">ML038 (CID 2946732). </p></div></div><p>From a recent survey of the literature and SciFinder patent search, there are very few examples of intestinal alkaline phosphatase (IAP) inhibitors (and no activators) that show selectivity for the target over the other alkaline phosphatase isozymes (PLAP, TNAP) in the literature. A recent disclosure of modulators, i.e., activators and inhibitors, of Intestinal Alkaline Phosphatase (IAP) describes classes of molecules that can be used for treating bacterial infections of the intestinal tract and methods for maintaining the health of the intestinal tract using IAP activators. However, no selectivity data is presented for these compounds. Further disclosed are methods to assist in weight gain of emaciated patients and those having reduced or negligible fat absorption using IAP inhibitors (US2010/0016313 A1). A representative molecule from this patent is illustrated in <a class="figpopup" href="/books/NBK143562/figure/ml260.f7/?report=objectonly" target="object" rid-figpopup="figml260f7" rid-ob="figobml260f7">Figure 7</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml260f7" co-legend-rid="figlgndml260f7"><a href="/books/NBK143562/figure/ml260.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml260f7" rid-ob="figobml260f7"><img class="small-thumb" src="/books/NBK143562/bin/ml260f7.gif" src-large="/books/NBK143562/bin/ml260f7.jpg" alt="Figure 7. Representative molecule from patent US2010/0016313 A1." /></a><div class="icnblk_cntnt" id="figlgndml260f7"><h4 id="ml260.f7"><a href="/books/NBK143562/figure/ml260.f7/?report=objectonly" target="object" rid-ob="figobml260f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Representative molecule from patent US2010/0016313 A1. </p></div></div><p>The probe described in this report represents a novel, chemically distinct, first-in-class inhibitor probe <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> of the mouse IAP isozyme, that is the most potent, sub-micromolar (muIAP IC<sub>50</sub> = 540 nM), and selective inhibitor reported for the enzyme from this species. As a comparison, its potency (muIAP IC<sub>50</sub> = 540 nM) for the mouse IAP, is comparable to that of the previous MLSCN probe <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a> (huIAP IC<sub>50</sub> = 122 nM) for the human enzyme, however it represents significant improvements in selectivity against the other isozymes, TNAP (65-fold <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> vs. 6.5-fold <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a>) and PLAP (>185-fold <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> vs. 39-fold <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a>). However, it should be noted that this probe is highly selective for the mouse <i>vs.</i> the human isoform. Our lab (Dr. Millán) has shown that the phylogenetic analysis shows that the mouse isozymes are closer in homology to each other than to the human isozymes [5], so our finding of such a species selective probe for muIAP validates this on an enzyme functional level. Also, the dihydrobenzo[d]oxazole-6-sulfonamido-acetamide core of <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> represents a completely different chemical scaffold as compared to the triazole scaffold of <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a>, so it will potentially offer a pharmacophore with different ADME/T PK properties than <a href="/pcsubstance/?term=ML038[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML038</a>. Indeed <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> has excellent solubility and stability properties.</p></div></div><div id="ml260.s19"><h2 id="_ml260_s19_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml260.r1">Low MG, Prasad AR. A phospholipase D specific for the phosphatidylinositol anchor of cell-surface proteins is abundant in plasma. <span><span class="ref-journal">Proc Natl Acad Sci USA. </span>1988;<span class="ref-vol">85</span>:980–984.</span> [<a href="/pmc/articles/PMC279684/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC279684</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/3422494" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3422494</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml260.r2">Millan JL. Alkaline Phosphatases: Structure, substrate specificity and functional relatedness to other members of a large super family of enzymes. <span><span class="ref-journal">In Purinergic Signalling. </span>2006;<span class="ref-vol">2</span>(2):335–341.</span> [Review] [<a href="/pmc/articles/PMC2254479/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2254479</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18404473" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18404473</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml260.r3">Goldberg RF, Austen WG Jr, Zhang X, Munene G, Mostafa G, Biswas S, McCormack M, Eberlin K, Nguyen JT, Tatlidede HS, Warren HS, Malo MS, Narisawa S, Millán JL, Hodin RA. Intestinal alkaline phosphatase is a gut defense factor maintained by enteral nutrition. <span><span class="ref-journal">Proc Natl Acad Sci USA. </span>2008;<span class="ref-vol">105</span>:3551–3556.</span> [<a href="/pmc/articles/PMC2265168/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2265168</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18292227" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18292227</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml260.r4">Narisawa S, Huang L, Iwasaki A, Hasegawa H, Alpers DH, Millán JL. Accelerated fat absorption in intestinal alkaline phosphatase knockout mice. <span><span class="ref-journal">Mol Cell Biol. </span>2003;<span class="ref-vol">23</span>:7525–7530.</span> [<a href="/pmc/articles/PMC207564/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC207564</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14560000" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14560000</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml260.r5">Narisawa S, Hoylaerts MF, Doctor KS, Fukuda MN, Alpers DH, Millán JL. A novel phosphatase upregulated in Akp3 knockout mice. <span><span class="ref-journal">Am J Physiol Gastrointest Liver Physiol. </span>2007;<span class="ref-vol">293</span>:1068–77.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17901166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17901166</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml260.r6">Nakano T, Inoue I, Koyama I, Kanazawa K, Nakamura K, Narisawa S, Tanaka K, Akita M, Masuyama T, Seo M, Hokari S, Katayama S, Alpers DH, Millán JL, Komoda T. Disruption of the murine intestinal alkaline phosphatase gene (Akp3) impairs lipid transcytosis and induces visceral fat accumulation and hepatic steatosis. <span><span class="ref-journal">Am J Physiol Gastrointest Liver Physiol. </span>2007;<span class="ref-vol">292</span>:1439–1449.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17332477" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17332477</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml260.r7">Akiba Y, Watanabe C, Mizumori M, Kaunitz JD. Luminal L-glutamate enhances duodenal mucosal defense mechanisms via multiple glutamate receptors in rats. <span><span class="ref-journal">Am J Physiol Gastrointest Liver Physiol. </span>2009;<span class="ref-vol">297</span>(4):G781–791.</span> [<a href="/pmc/articles/PMC2763813/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2763813</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19643955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19643955</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml260.r8">Mizumori M, Ham M, Guth PH, Engel E, Kaunitz JD, Akiba Y. Intestinal alkaline phosphatase regulates protective surface microclimate pH in rat duodenum. <span><span class="ref-journal">J Physiol. </span>2009;<span class="ref-vol">587</span>(Pt 14):3651–63.</span> Epub 2009 May 18. [<a href="/pmc/articles/PMC2742288/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2742288</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19451200" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19451200</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143562_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Santhi Ganji</span>,<sup>1</sup> <span itemprop="author">Jiwen Zou</span>,<sup>1</sup> <span itemprop="author">Brock Brown</span>,<sup>1</sup> <span itemprop="author">Ekaterina V. Bobkova</span>,<sup>1</sup> <span itemprop="author">Robert Ardecky</span>,<sup>1</sup> <span itemprop="author">Craig Rosenstein</span>,<sup>2</sup> <span itemprop="author">Ian Pass</span>,<sup>1</sup> <span itemprop="author">Russell Dahl</span>,<sup>1</sup> <span itemprop="author">Stefan Vasile</span>,<sup>2</sup> <span itemprop="author">Eduard Sergienko</span>,<sup>1</sup> <span itemprop="author">Shenghua Shi</span>,<sup>1</sup> <span itemprop="author">Derek Stonich</span>,<sup>1</sup> <span itemprop="author">Anton Cheltov</span>,<sup>1</sup> <span itemprop="author">Ying Su</span>,<sup>1</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>2</sup> <span itemprop="author">Michael Vicchiarelli</span>,<sup>2</sup> <span itemprop="author">Danielle McAnally</span>,<sup>2</sup> <span itemprop="author">Sylvia Kim</span>,<sup>1</sup> <span itemprop="author">Hung Nguyen</span>,<sup>1</sup> <span itemprop="author">Tina Kiffer Moreira</span>,<sup>3</sup> <span itemprop="author">Layton H. Smith</span>,<sup>2</sup> <span itemprop="author">Fu-Yue Zeng</span>,<sup>1</sup> <span itemprop="author">Jena Diwan</span>,<sup>1</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>1</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>1</sup> <span itemprop="author">Jonathan Kaunitz</span>,<sup>4</sup> and <span itemprop="author">José Luis Millán</span><sup>3</sup>.<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></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, La Jolla, California 92037, USA.</div><div class="affiliation"><sup>2</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>3</sup>
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Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.</div><div class="affiliation"><sup>4</sup>
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University of California, Los Angeles, School of Medicine, Veterans Hospital, Los Angeles, CA 90073</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author: Anthony B. Pinkerton, 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@notreknipa" class="oemail">gro.mahnrubdrofnas@notreknipa</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">October 31, 2011</span>; Last Update: <span itemprop="dateModified">March 7, 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>Ganji S, Zou J, Brown B, et al. A Selective Murine Intestinal Alkaline Phosphatase (muIAP) Inhibitor. 2011 Oct 31 [Updated 2013 Mar 7]. 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/ml262/?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/ml258/?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="figobml260fu1"><div id="ml260.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260fu1.jpg" alt="Image ml260fu1" /></div></div></article><article data-type="table-wrap" id="figobml260t1"><div id="ml260.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Biological activity summary & AIDs for Probes</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143562/table/ml260.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml260.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml260.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml260.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml260.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">muIAP inhibitor IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml260.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml260.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Other alkaline phosphatases IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml260.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th></tr></thead><tbody><tr><td headers="hd_h_ml260.t1_1_1_1_1" rowspan="3" colspan="1" style="text-align:center;vertical-align:top;">CID 5091937<br /><a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a></td><td headers="hd_h_ml260.t1_1_1_1_2" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">muIAP inhibitor (mouse)</td><td headers="hd_h_ml260.t1_1_1_1_3" rowspan="3" colspan="1" style="text-align:left;vertical-align:top;">540 nM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588647" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588647</a></td><td headers="hd_h_ml260.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TNAP<br />Inhibitor</td><td headers="hd_h_ml260.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">35 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588639" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588639</a></td><td headers="hd_h_ml260.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">65 vs. TNAP</td></tr><tr><td headers="hd_h_ml260.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PLAP<br />Inhibitor</td><td headers="hd_h_ml260.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>100 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588641" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588641</a></td><td headers="hd_h_ml260.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>185 vs. PLAP</td></tr><tr><td headers="hd_h_ml260.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">huIAP (human)<br />Inhibitor</td><td headers="hd_h_ml260.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>100 μM<br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588645" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588645</a></td><td headers="hd_h_ml260.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>185 vs. huIAP</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml260t2"><div id="ml260.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Summary of Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143562/table/ml260.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml260.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th><th id="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Responsible Center</th></tr></thead><tbody><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary assay for identification of inhibitors of <u>mouse intestinal alkaline phosphatase</u>.</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2818" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2818</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS Luminescent assay for identification of inhibitors of <u>mouse intestinal alkaline phosphatase</u></td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2806" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2806</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Single concentration confirmation of uHTS hits from a small molecule inhibitors of <u>mouse intestinal alkaline phosphatase</u> via a luminescent assay</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/434971" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 434971</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Cherry Pick)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose Response confirmation of uHTS hits from a small molecule inhibitors of <u>mouse intestinal alkaline phosphatase</u> via a luminescent assay</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488785" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488785</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (DMSO Dose Response)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule inhibitors of <u>mouse intestinal alkaline phosphatase</u> via a luminescent assay</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493135" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493135</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588647" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588647</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dry Powder)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose Response confirmation of uHTS inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Placental Alkaline Phosphatase</u></td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488879" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488879</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (DMSO Dose Response)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Placental Alkaline Phosphatase</u></td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493136" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493136</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588641" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588641</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (Dry Powder)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose Response confirmation of uHTS inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Tissue Nonspecific Alkaline Phosphatase</u>.</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488906" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488906</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (DMSO Dose Response)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Tissue Nonspecific Alkaline Phosphatase</u>.</td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493148" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493148</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588639" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588639</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (Dry Powder)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose Response confirmation of uHTS inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Human Intestinal Alkaline Phosphatase</u></td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488876" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488876</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (DMSO Dose Response)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr><tr><td headers="hd_h_ml260.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule inhibitors of Mouse Intestinal Alkaline Phosphatase using <u>Human Intestinal Alkaline Phosphatase</u></td><td headers="hd_h_ml260.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493144" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493144</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588645" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588645</a></td><td headers="hd_h_ml260.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Inhibitor</td><td headers="hd_h_ml260.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Selectivity (Dry Powder)</td><td headers="hd_h_ml260.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Biochemical</td><td headers="hd_h_ml260.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Chemiluminescence & 1536 well</td><td headers="hd_h_ml260.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SBCCG</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml260f1"><div id="ml260.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f1.jpg" alt="Figure 1. Structure of ML260." /></div><h3><span class="label">Figure 1</span><span class="title">Structure of ML260</span></h3></div></article><article data-type="table-wrap" id="figobml260t3"><div id="ml260.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Probe and Analog Submissions to MLSMR (BioFocus DPI) for muIAP Inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143562/table/ml260.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml260.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml260.t3_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:middle;">Probe - CID 50919367</th></tr><tr><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (BCCG)</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source (vendor or synthesized)</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml260.t3_1_1_1_1" id="hd_h_ml260.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_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Probe<br /><a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0454667</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873799</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 50919367</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/124756790" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 124756790</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">26.6</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr><tr><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 1</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0454682</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873800</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 24790974</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/117695555" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 117695555</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.7</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr><tr><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 2</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0454689</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873801</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 51035365</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/117695562" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 117695562</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">21.9</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr><tr><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 3</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0454687</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873802</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 24790980</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/117695560" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 117695560</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.4</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr><tr><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 4</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0454683</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873803</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 51035367</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/125311365" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311365</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">22.5</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr><tr><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Analog 5</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0466802</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS003873804</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 53384787</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.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/125311575" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311575</a></td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Synthesized</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.8</td><td headers="hd_h_ml260.t3_1_1_1_1 hd_h_ml260.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10/25/2011</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml260f8"><div id="ml260.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f8.jpg" alt="Scheme 1. Synthesis of ML260." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of ML260</span></h3><div class="caption"><p>conditions: <b>a</b>. dichloromethane, triethylamine, (88% yield); <b>b</b>. trifluoroacetic acid, dichloromethane, 0°C warm to RT (100% yield); <b>c</b>. EDC, HOBT, NMM, DMF, (55%)</p></div></div></article><article data-type="fig" id="figobml260f2"><div id="ml260.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f2.jpg" alt="Figure 2. 1H NMR Spectrum of ML260." /></div><h3><span class="label">Figure 2</span><span class="title"><sup>1</sup>H NMR Spectrum of ML260</span></h3></div></article><article data-type="fig" id="figobml260f3"><div id="ml260.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20LC-MS%20for%20ML260.&p=BOOKS&id=143562_ml260f3.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/NBK143562/bin/ml260f3.jpg" alt="Figure 3. LC-MS for ML260." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">LC-MS for ML260</span></h3><div class="caption"><p>(Reverse phase C18 column: isocratic)</p></div></div></article><article data-type="fig" id="figobml260f4"><div id="ml260.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Stability%20of%20ML260%20in%201%3A1%20acetonitrile%3APBS%20at%20room%20temperature.&p=BOOKS&id=143562_ml260f4.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/NBK143562/bin/ml260f4.jpg" alt="Figure 4. Stability of ML260 in 1:1 acetonitrile:PBS at room temperature." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Stability of ML260 in 1:1 acetonitrile:PBS at room temperature</span></h3></div></article><article data-type="fig" id="figobml260fu2"><div id="ml260.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260fu2.jpg" alt="Image ml260fu2" /></div></div></article><article data-type="fig" id="figobml260fu3"><div id="ml260.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260fu3.jpg" alt="Image ml260fu3" /></div></div></article><article data-type="fig" id="figobml260fu4"><div id="ml260.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260fu4.jpg" alt="Image ml260fu4" /></div></div></article><article data-type="fig" id="figobml260f5"><div id="ml260.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f5.jpg" alt="Figure 5. Multiple dose response titrations of ML260." /></div><h3><span class="label">Figure 5</span><span class="title">Multiple dose response titrations of ML260</span></h3></div></article><article data-type="table-wrap" id="figobml260t4"><div id="ml260.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Summary of <i>in vitro</i> ADME Properties of Novel Selection of muIAP Inhibitor Probe ML260</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143562/table/ml260.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml260.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml260.t4_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml260.t4_1_1_1_1" style="text-align:center;vertical-align:top;">Probe<br />Probe ML#<br />SBCCG MLS-#</th><th id="hd_h_ml260.t4_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml260.t4_1_1_1_2" style="text-align:center;vertical-align:top;">Aqueous Solubility<br />μg/mL<br /><i>[μM]</i><sup>a</sup><br />@pH5.0/6.2/7.4</th><th id="hd_h_ml260.t4_1_1_1_3" rowspan="2" colspan="1" headers="hd_h_ml260.t4_1_1_1_3" style="text-align:center;vertical-align:top;">PAMPA<br />Pe<br />(x10<sup>−6</sup> cm/s)<br />Donor pH: 5.0/6.2/7.4<br />Acceptor<br />pH: 7.4</th><th id="hd_h_ml260.t4_1_1_1_4" colspan="2" rowspan="1" style="text-align:center;vertical-align:top;">Plasma Protein Binding (% Bound)</th><th id="hd_h_ml260.t4_1_1_1_5" rowspan="2" colspan="1" headers="hd_h_ml260.t4_1_1_1_5" style="text-align:center;vertical-align:top;">Plasma Stability<br />(%Remaining @3hrs)<br />Human/Mouse<br />Plasma:1× PBS, pH 7.4, 1:1</th><th id="hd_h_ml260.t4_1_1_1_6" rowspan="2" colspan="1" headers="hd_h_ml260.t4_1_1_1_6" style="text-align:center;vertical-align:top;">Hepatic Microsome Stability<br />Human/Mouse<br />% remaining @ 1 hr 37°C.</th></tr><tr><th headers="hd_h_ml260.t4_1_1_1_4" id="hd_h_ml260.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Human<br />1μM/10 μM</th><th headers="hd_h_ml260.t4_1_1_1_4" id="hd_h_ml260.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Mouse<br />1μM/10 μM</th></tr></thead><tbody><tr><td headers="hd_h_ml260.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 50919367<br /><a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a><br />MLS-0454667</td><td headers="hd_h_ml260.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">81/108/>186<br />[216/288/>496]</td><td headers="hd_h_ml260.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6.1/3.6/<0.9</td><td headers="hd_h_ml260.t4_1_1_1_4 hd_h_ml260.t4_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">97/97</td><td headers="hd_h_ml260.t4_1_1_1_4 hd_h_ml260.t4_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND<sup>*</sup></td><td headers="hd_h_ml260.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">95/1<sup>**</sup></td><td headers="hd_h_ml260.t4_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15/75</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="ml260.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 class="bkr_refwrap"><dt>*</dt><dd><div id="ml260.tfn2"><p class="no_margin">N.D. – not determinable, as less <a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> was present in the plasma donor chamber vs. reference buffer chamber at end of incubation time, consistent with the instability noted in mouse plasma.</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml260.tfn3"><p class="no_margin"><a href="/pcsubstance/?term=ML260[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML260</a> is completely stable in the absence of plasma in 1X PBS:acetonitrile (see <a class="figpopup" href="/books/NBK143562/figure/ml260.f2/?report=objectonly" target="object" rid-figpopup="figml260f2" rid-ob="figobml260f2">Fig. 2</a>)</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml260f6"><div id="ml260.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f6.jpg" alt="Figure 6. ML038 (CID 2946732)." /></div><h3><span class="label">Figure 6</span><span class="title">ML038 (CID 2946732)</span></h3></div></article><article data-type="fig" id="figobml260f7"><div id="ml260.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143562/bin/ml260f7.jpg" alt="Figure 7. Representative molecule from patent US2010/0016313 A1." /></div><h3><span class="label">Figure 7</span><span class="title">Representative molecule from patent US2010/0016313 A1</span></h3></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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