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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK190602" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK190602/" /><meta name="ncbi_pagename" content="Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<title>Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2014/01/13" /><meta name="citation_author" content="Ganesha Rai" /><meta name="citation_author" content="Netra Joshi" /><meta name="citation_author" content="Steve Perry" /><meta name="citation_author" content="Adam Yasgar" /><meta name="citation_author" content="Lena Schultz" /><meta name="citation_author" content="Jog Eun Jung" /><meta name="citation_author" content="Yu Liu" /><meta name="citation_author" content="Yasukazu Terasaki" /><meta name="citation_author" content="Giovanni Diaz" /><meta name="citation_author" content="Victor Kenyon" /><meta name="citation_author" content="Ajit Jadhav" /><meta name="citation_author" content="Anton Simeonov" /><meta name="citation_author" content="Klaus van Leyen" /><meta name="citation_author" content="Theodore R. Holman" /><meta name="citation_author" content="David J. Maloney" /><meta name="citation_pmid" content="24672829" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK190602/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Ganesha Rai" /><meta name="DC.Contributor" content="Netra Joshi" /><meta name="DC.Contributor" content="Steve Perry" /><meta name="DC.Contributor" content="Adam Yasgar" /><meta name="DC.Contributor" content="Lena Schultz" /><meta name="DC.Contributor" content="Jog Eun Jung" /><meta name="DC.Contributor" content="Yu Liu" /><meta name="DC.Contributor" content="Yasukazu Terasaki" /><meta name="DC.Contributor" content="Giovanni Diaz" /><meta name="DC.Contributor" content="Victor Kenyon" /><meta name="DC.Contributor" content="Ajit Jadhav" /><meta name="DC.Contributor" content="Anton Simeonov" /><meta name="DC.Contributor" content="Klaus van Leyen" /><meta name="DC.Contributor" content="Theodore R. Holman" /><meta name="DC.Contributor" content="David J. Maloney" /><meta name="DC.Date" content="2014/01/13" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK190602/" /><meta name="description" content="Lipoxygenases (e.g. 5, 12 and 15-LOX-1) are implicated in a number of human diseases, with reticulocyte 15-Lipoxygenase-1 (15-LOX-1 or 12/15-LOX) being specifically involved in cancer, atherosclerosis, and neurodegenerative conditions, such as stroke [1-9]. Despite the potential therapeutic relevance of this target, few potent, selective and cell-active inhibitors have been reported. Toward this end, we employed a quantitative high-throughput (qHTS) screen against ∼74,000 small molecules which led to the discovery of ML351, a novel chemotype for 15-LOX-1 inhibition, that displays nanomolar potency (IC50 = 200 nM) and excellent selectivity (>250-fold) versus the related isozymes, 5-LOX, platelet 12-LOX, 15-LOX-2, ovine COX-1, and human COX-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is a tight binding, mixed inhibitor, which does not reduce the active-site ferric ion. Finally, ML351 protected against oxidative glutamate toxicity in mouse neuronal cells (HT-22) and significantly reduced infarct size in an in vivo mouse model for ischemic stroke. As such, ML351 represents the first report of a selective inhibitor of 15-LOX-1 with demonstrated in vivo activity in proof-of-concept models of stroke." /><meta name="og:title" content="Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1" /><meta name="og:type" content="book" /><meta name="og:description" content="Lipoxygenases (e.g. 5, 12 and 15-LOX-1) are implicated in a number of human diseases, with reticulocyte 15-Lipoxygenase-1 (15-LOX-1 or 12/15-LOX) being specifically involved in cancer, atherosclerosis, and neurodegenerative conditions, such as stroke [1-9]. Despite the potential therapeutic relevance of this target, few potent, selective and cell-active inhibitors have been reported. Toward this end, we employed a quantitative high-throughput (qHTS) screen against ∼74,000 small molecules which led to the discovery of ML351, a novel chemotype for 15-LOX-1 inhibition, that displays nanomolar potency (IC50 = 200 nM) and excellent selectivity (>250-fold) versus the related isozymes, 5-LOX, platelet 12-LOX, 15-LOX-2, ovine COX-1, and human COX-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is a tight binding, mixed inhibitor, which does not reduce the active-site ferric ion. Finally, ML351 protected against oxidative glutamate toxicity in mouse neuronal cells (HT-22) and significantly reduced infarct size in an in vivo mouse model for ischemic stroke. As such, ML351 represents the first report of a selective inhibitor of 15-LOX-1 with demonstrated in vivo activity in proof-of-concept models of stroke." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK190602/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml351/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK190602/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK190602_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK190602_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml353/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml350/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK190602_"><span class="title" itemprop="name">Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1</span></h1><p class="contrib-group"><span itemprop="author">Ganesha Rai</span>, <span itemprop="author">Netra Joshi</span>, <span itemprop="author">Steve Perry</span>, <span itemprop="author">Adam Yasgar</span>, <span itemprop="author">Lena Schultz</span>, <span itemprop="author">Jog Eun Jung</span>, <span itemprop="author">Yu Liu</span>, <span itemprop="author">Yasukazu Terasaki</span>, <span itemprop="author">Giovanni Diaz</span>, <span itemprop="author">Victor Kenyon</span>, <span itemprop="author">Ajit Jadhav</span>, <span itemprop="author">Anton Simeonov</span>, <span itemprop="author">Klaus van Leyen</span>, <span itemprop="author">Theodore R. Holman</span>, and <span itemprop="author">David J. Maloney</span>.</p><a data-jig="ncbitoggler" href="#__NBK190602_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK190602_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Ganesha Rai</span>,<sup>1</sup> <span itemprop="author">Netra Joshi</span>,<sup>2</sup> <span itemprop="author">Steve Perry</span>,<sup>2</sup> <span itemprop="author">Adam Yasgar</span>,<sup>1</sup> <span itemprop="author">Lena Schultz</span>,<sup>1</sup> <span itemprop="author">Jog Eun Jung</span>,<sup>3</sup> <span itemprop="author">Yu Liu</span>,<sup>3</sup> <span itemprop="author">Yasukazu Terasaki</span>,<sup>3</sup> <span itemprop="author">Giovanni Diaz</span>,<sup>2</sup> <span itemprop="author">Victor Kenyon</span>,<sup>2</sup> <span itemprop="author">Ajit Jadhav</span>,<sup>1</sup> <span itemprop="author">Anton Simeonov</span>,<sup>1</sup> <span itemprop="author">Klaus van Leyen</span>,<sup>3</sup> <span itemprop="author">Theodore R. Holman</span>,<sup>2</sup> and <span itemprop="author">David J. Maloney</span><sup>1</sup><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD</div><div class="affiliation"><sup>2</sup>
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Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA</div><div class="affiliation"><sup>3</sup>
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Neuroprotection Research Laboratory, Massachusetts General Hospital, Charlestown, MA</div><div class="affiliation">
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<sup>*</sup> To whom correspondence should be addressed: Email:
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<a href="mailto:dev@null" data-email="vog.hin.liam@dyenolam" class="oemail">vog.hin.liam@dyenolam</a></div></div><p class="small">Received: <span itemprop="datePublished">April 15, 2013</span>; Last Update: <span itemprop="dateModified">January 13, 2014</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Lipoxygenases (e.g. 5, 12 and 15-LOX-1) are implicated in a number of human diseases, with reticulocyte 15-Lipoxygenase-1 (15-LOX-1 or 12/15-LOX) being specifically involved in cancer, atherosclerosis, and neurodegenerative conditions, such as stroke [<a class="bk_pop" href="#ml351.r1">1</a>-<a class="bk_pop" href="#ml351.r9">9</a>]. Despite the potential therapeutic relevance of this target, few potent, selective and cell-active inhibitors have been reported. Toward this end, we employed a quantitative high-throughput (qHTS) screen against ∼74,000 small molecules which led to the discovery of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a>, a novel chemotype for 15-LOX-1 inhibition, that displays nanomolar potency (IC<sub>50</sub> = 200 nM) and excellent selectivity (>250-fold) versus the related isozymes, 5-LOX, platelet 12-LOX, 15-LOX-2, ovine COX-1, and human COX-2. In addition, kinetic experiments were performed which indicate that this class of inhibitor is a tight binding, mixed inhibitor, which does not reduce the active-site ferric ion. Finally, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> protected against oxidative glutamate toxicity in mouse neuronal cells (HT-22) and significantly reduced infarct size in an <i>in vivo</i> mouse model for ischemic stroke. As such, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> represents the first report of a <i>selective</i> inhibitor of 15-LOX-1 with demonstrated <i>in vivo</i> activity in proof-of-concept models of stroke.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> <a href="/nuccore/1365464663" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">MH081283</a></p><p><b>Version #:</b> 1</p><p><b>Date Submitted:</b> 04/15/2013</p><p><b>Screening Center Name & PI:</b> NIH Chemical Genomics Center, Christopher P. Austin</p><p><b>Chemistry Center Name & PI:</b> NIH Chemical Genomics Center, Christopher P. Austin</p><p><b>Assay Submitter & Institution:</b> Theodore R. Holman, University of California, Santa Cruz.</p><p>PubChem Summary Bioassay Identifier (AID): <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2169" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2169</a></p><div id="ml351.s1"><h2 id="_ml351_s1_">Probe Structure & Characteristics</h2><div id="ml351.f1" class="figure"><div class="graphic"><img src="/books/NBK190602/bin/ml351f1.jpg" alt="Image ml351f1" /></div></div><div id="ml351.t1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK190602/table/ml351.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml351.t1_lrgtbl__"><table><thead><tr><th id="hd_h_ml351.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML#</th><th id="hd_h_ml351.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml351.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml351.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target Name(s)</th><th id="hd_h_ml351.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC50/EC50 (μM) [SID, AID]</th><th id="hd_h_ml351.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective</th><th id="hd_h_ml351.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml351.t1_1_1_1_1" rowspan="4" colspan="1" style="text-align:left;vertical-align:top;">CID 664510 / <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a></td><td headers="hd_h_ml351.t1_1_1_1_2" rowspan="4" colspan="1" style="text-align:left;vertical-align:top;">15-LOX-1</td><td headers="hd_h_ml351.t1_1_1_1_3" rowspan="4" colspan="1" style="text-align:left;vertical-align:top;">200 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493219" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493219</a>]</td><td headers="hd_h_ml351.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12-LOX</td><td headers="hd_h_ml351.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">> 100[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493216" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493216</a>]</td><td headers="hd_h_ml351.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>500</td><td headers="hd_h_ml351.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">12-LOX [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493216" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493216</a>]</td></tr><tr><td headers="hd_h_ml351.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">15-LOX-2</td><td headers="hd_h_ml351.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>100 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493220" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493220</a>]</td><td headers="hd_h_ml351.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>500</td><td headers="hd_h_ml351.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">15-LOX-2 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493220" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493220</a>]</td></tr><tr><td headers="hd_h_ml351.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5-LOX</td><td headers="hd_h_ml351.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>]</td><td headers="hd_h_ml351.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>250</td><td headers="hd_h_ml351.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5-LOX [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>]</td></tr><tr><td headers="hd_h_ml351.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">COX-1/2</td><td headers="hd_h_ml351.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><10% inhibition at 15 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 104223766</a>]</td><td headers="hd_h_ml351.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml351.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></div><div id="ml351.s2"><h2 id="_ml351_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a>, exhibits potent and selective inhibition of 15-LOX-1 <i>in vitro</i> and demonstrates favorable cell permeability and activity in cell-based assays which enables researchers to study the role of 15-LOX-1 in a variety of biological systems. 15-LOX-1 has been implicated in the pathophysiology of stroke and neurodegenerative disorders (e.g. Alzheimer's and Parkinson's disease). As such, targeted inhibition of 15-LOX-1 has been proposed as a therapeutic strategy to mitigate the effects of these diseases by acting as neuroprotective agents. Importantly, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> has been shown to protect cells from oxidative stress-related neuronal cell death, efficiently cross the BBB, and significantly reduce infarct size in mouse models of stroke. These data suggest that <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> can be used to probe the effects of 15-LOX-1 inhibition in animal models for a variety of neurodegenerative diseases.</p></div><div id="ml351.s3"><h2 id="_ml351_s3_">2. Materials and Methods</h2><p><b>General Methods for Chemistry:</b> All air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Anhydrous solvents such as dichloromethane, <i>N,N</i>-dimethylforamide (DMF), acetonitrile, methanol and triethylamine were purchased from Sigma-Aldrich. Preparative purification was performed on a Waters semi-preparative HPLC system. The column used was a Phenomenex Luna C18 (5 micron, 30 × 75 mm) at a flow rate of 45 mL/min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220 nm). Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA). Method 1: A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an 8 minute run time at a flow rate of 1 mL/min. A Phenomenex Luna C18 column (3 micron, 3 × 75 mm) was used at a temperature of 50 °C. Method 2: A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 mL/min. A Phenomenex Gemini Phenyl column (3 micron, 3 × 100 mm) was used at a temperature of 50 °C. Purity determination was performed using an Agilent Diode Array Detector for both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. <sup>1</sup>H NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical shifts are reported in ppm with undeuterated solvent (DMSO-d<sub>6</sub> at 2.49 ppm) as internal standard for DMSO-<i>d</i><sub>6</sub> solutions. All of the analogs tested in the biological assays have purity greater than 95%, based on both analytical methods. High resolution mass spectrometry was recorded on Agilent 6210 Time-of-Flight LC/MS system. Confirmation of molecular formula was accomplished using electrospray ionization in the positive mode with the Agilent Masshunter software (version B.02).</p><div id="ml351.s4"><h3>2.1. Assays</h3><p><b>15-Lipoxygenase-1 qHTS Assay (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/887" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 887</a>).</b> All screening operations were performed on a fully integrated robotic system (Kalypsys Inc., San Diego, CA). Three micoliter of enzyme (40 nM 15-hLO-1, final concentration) was dispensed into a 1536-well Greiner black clear-bottom assay plate. Then compounds and controls (23 nL) were transferred via Kalypsys pintool equipped with 1536-pin array. The plate was incubated for 15 min at room temperature, and then a 1 μL aliquot of substrate solution (final concentration of 50 μM arachidonic acid) was added to start the reaction. The reaction was stopped after 6.5 min by the addition of 4 μL of FeXO solution (final concentrations of 200 μM Xylenol Orange (XO) and 300 μM ferrous ammonium sulfate in 50 mM sulfuric acid). The assay plate was incubated at room temperature for 30 min. The absorbances at 405 and 573 nm were recorded using ViewLux high throughput CCD imager (Perkin-Elmer, Waltham, MA) using standard absorbance protocol settings. Plates containing DMSO only were included approximately every 50 plates throughout the qHTS to monitor any systematic trend in the assay signal associated with reagent dispenser variation or decrease in enzyme specific activity. Data was normalized to known positive control and DMSO treated wells for negative control.</p><p><b>Lipoxygenase UV-Vis Assay.</b> The inhibitors were screened initially using one concentration point on a Perkin-Elmer Lambda 40 UV/Vis spectrophotometer. The percent inhibition was determined by comparing the enzyme rates of the control (DMSO solvent) and the inhibitor sample by following the formation of the conjugated diene product at 234 nm (ε = 25,000 M<sup>-1</sup>cm<sup>-1</sup>). The reactions were initiated by adding either of ∼ 40 nM 12-LOX, 40 nM 15-LOX-1, 0.5 μM 15-LOX-2 or 5-10 μL of 5-LOX crude extract to a cuvette with a 2 mL reaction buffer constantly stirred using a magnetic stir bar at room temperature (22 °C). Reaction buffers used for various lipoxygenase were as follows- 25 mM HEPES (pH 7.3), 0.3 mM CaCl<sub>2</sub>, 0.1 mM EDTA, 0.2 mM ATP, 0.01% Triton X-100, 10 μM AA for the crude, ammonium sulfate precipitated 5-LOX; 25 mM Hepes (pH 8), 0.01% Triton X-100, 10 μM AA for 12-LOX and 25 mM Hepes buffer (pH 7.5), 0.01% Triton X-100, 10 µM AA for 15-LOX-1 and 15-LOX-2. The substrate concentration was quantitatively determined by allowing the enzymatic reaction to go to completion in the presence of 15-LOX-2. For the inhibitors that showed more than 50% inhibition at the one point screens, IC<sub>50</sub> values were obtained by determining the enzymatic rate at various inhibitor concentrations and plotted against inhibitor concentration, followed by a hyperbolic saturation curve fit (assuming total enzyme concentration [E] << <i>K</i><sub>i</sub><sup>app</sup>, so IC<sub>50</sub> ∼ <i>K</i><sub>i</sub><sup>app</sup> ).</p><p><b>HT22 Cell Culture.</b> Glutathione depletion was induced in HT22 cells by glutamate treatment, and LDH release into the medium was measured to detect cell death as described. HT22 cells were cultured in DMEM containing 10% fetal bovine serum and penicillin/streptomycin. For viability experiments, cells were seeded at 1 × 10<sup>4</sup> cells/well in 96-well plates and treated 18 hr later, when the cells were approximately 50-70% confluent. Treatment consisted of exchanging the medium to 100 μL fresh culturing medium and adding 5 mM glutamate in the presence or absence of DMSO (maximum 0.1% final concentration) as control or the indicated concentrations of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a>. Lactate dehydrogenase (LDH) content was determined separately for the cell extracts and corresponding media using a Cytotoxicity Detection Kit, and the percentage of LDH released to the medium calculated after subtracting the corresponding background value. To determine levels of the 12/15-LOX metabolite 12-hydroxy-eicosatetraenoic acid (12-HETE), we cultured HT22 cells in 75 cm<sup>2</sup> flasks in DMEM medium without phenol red, supplemented with 5% FBS, and treated the cells the next day when cells were 50-70% confluent. 24 hours later, the eicosanoid-containing fraction was isolated via Sep-Pak C-18 column, and 12-HETE was detected with a 12-HETE ELISA kit, used according to the manufacturer's instruction. Three independent experiments were evaluated.</p></div><div id="ml351.s5"><h3>2.2. Probe Chemical Characterization</h3><div id="ml351.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK190602/bin/ml351f2.jpg" alt="*Purity >98% as determined by LC/MS and 1H NMR analyses" /></div><div class="caption"><p>*Purity >98% as determined by LC/MS and <sup>1</sup>H NMR analyses.</p></div></div><p><b><i>5-(methylamino)-2-(naphthalen-1-yl)oxazole-4-carbonitrile</i> (CID 664510):</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 6.011 min and t<sub>2</sub> (Method 2) = 2.42 min; <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ 9.15 (dq, <i>J</i> = 8.7 and 0.9 Hz, 1H), 8.44 (brs, 1H), 8.10 – 7.99 (m, 3H), 7.74 – 7.57 (m, 3H), 3.07 – 3.01 (m, 3H).; <sup>13</sup>C NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ 161.9, 161.9, 149.5, 134.1, 134.0, 131.2, 129.2, 128.3, 127.2, 127.2, 127.0, 126.9, 125.8, 125.8, 125.8, 125.7, 122.1, 116.5, 116.5, 84.1, 84.1, 84.1, 29.7, 29.7, 29.6; HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>15</sub>H<sub>12</sub>N<sub>3</sub>O, 250.0975; found 250.0975.</p><div id="ml351.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20Stability%20of%20ML351%20measured%20as%20percent%20composition%20of%20probe%20molecule%20in%20aqueous%20solution%20(contains%2020%20%25%20acetonitrile)%20at%20room%20temperature%20over%2048%20hr%20in%20(A)%20DPBS%20pH%207.4%20buffer%2C%20(b)%20Lipoxygenase%20UV-Vis%20assay%20buffer%20of%201M%20HEPES%20pH%207.3%2C%20(C)%20pH%202%20buffer%20and%20(D)%20pH%2010%20buffer.&p=BOOKS&id=190602_ml351f3.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/NBK190602/bin/ml351f3.jpg" alt="Figure 1. Stability of ML351 measured as percent composition of probe molecule in aqueous solution (contains 20 % acetonitrile) at room temperature over 48 hr in (A) DPBS pH 7.4 buffer, (b) Lipoxygenase UV-Vis assay buffer of 1M HEPES pH 7.3, (C) pH 2 buffer and (D) pH 10 buffer." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title">Stability of ML351 measured as percent composition of probe molecule in aqueous solution (contains 20 % acetonitrile) at room temperature over 48 hr in (A) DPBS pH 7.4 buffer, (b) Lipoxygenase UV-Vis assay buffer of 1M HEPES pH 7.3, (C) pH 2 buffer and (D) pH 10 buffer</span></h3><div class="caption"><p>Results showed good stability of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> in different types of buffers.</p></div></div><div id="ml351.f4" class="figure bk_fig"><div class="graphic"><img src="/books/NBK190602/bin/ml351f4.jpg" alt="Figure 2. Structures of the five ML351 analogs that have been submitted to the MLSMR with their corresponding Compound IDs and MLS IDs listed in Table 1." /></div><h3><span class="label">Figure 2</span><span class="title">Structures of the five ML351 analogs that have been submitted to the MLSMR with their corresponding Compound IDs and MLS IDs listed in <a class="figpopup" href="/books/NBK190602/table/ml351.t2/?report=objectonly" target="object" rid-figpopup="figml351t2" rid-ob="figobml351t2">Table 1</a></span></h3></div><div id="ml351.t2" class="table"><h3><span class="label">Table 1</span><span class="title">List of probe ML351 and related analogs that have been submitted to the MLSMR</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK190602/table/ml351.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml351.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Internal ID</th><th id="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MLS ID</th><th id="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th id="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ML #</th><th id="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Type</th><th id="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00070329</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813835</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223766" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223766</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">664510</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b><a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a></b></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Probe</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00262513</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813836</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160844115" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160844115</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70701467</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00319032</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813837</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160844145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160844145</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70701468</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00263290</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813838</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160844143" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160844143</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">63549790</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00263300</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813839</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160844143" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160844143</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70701476</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr><tr><td headers="hd_h_ml351.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>NCGC00263283</b></td><td headers="hd_h_ml351.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MLS004813840</td><td headers="hd_h_ml351.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/160844126" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160844126</a></td><td headers="hd_h_ml351.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">70701475</td><td headers="hd_h_ml351.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td><td headers="hd_h_ml351.t2_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Analog</td><td headers="hd_h_ml351.t2_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NCGC</td></tr></tbody></table></div></div></div><div id="ml351.s6"><h3>2.3. Probe Preparation</h3><p>Preparation of <b><i>5-(methylamino)-2-(naphthalen-1-yl)oxazole-4-carbonitrile</i> (<a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a>)</b> is a two-step process described below and illustrated in <a class="figpopup" href="/books/NBK190602/figure/ml351.f5/?report=objectonly" target="object" rid-figpopup="figml351f5" rid-ob="figobml351f5">Scheme 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml351f5" co-legend-rid="figlgndml351f5"><a href="/books/NBK190602/figure/ml351.f5/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml351f5" rid-ob="figobml351f5"><img class="small-thumb" src="/books/NBK190602/bin/ml351f5.gif" src-large="/books/NBK190602/bin/ml351f5.jpg" alt="Scheme 1. Synthetic route to ML351." /></a><div class="icnblk_cntnt" id="figlgndml351f5"><h4 id="ml351.f5"><a href="/books/NBK190602/figure/ml351.f5/?report=objectonly" target="object" rid-ob="figobml351f5">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthetic route to ML351. </p></div></div><ol class="upper-alpha"><li class="half_rhythm"><div>A mixture of 1-naphthoic acid and 2-aminomalononitrile.TsOH in ethyl acetate was added to triethanolamine (TEA) followed by 50 % solution of propylphosphonic anhydride (T<sub>3</sub>P<sup>®</sup>) in ethyl acetate. The reaction was allowed to stir at room temperature for 12 hr and was then diluted with ethyl acetate. The organic layer was successively washed with water, saturated bicarbonate solution, brine and dried with magnesium sulfate (MgSO<sub>4</sub>), and concentrated <i>in vacuo</i>. The crude product was purified on a biotage flash<sup>®</sup> system eluting with 50% ethyl acetate in hexanes containing 0.1 % triethylamine to provide the yellow solid 5-amino-2-(naphthalen-1-yl)oxazole-4-carbonitrile intermediate with 81% yield.</div></li><li class="half_rhythm"><div>A mixture of 5-amino-2-(naphthalen-1-yl)oxazole-4-carbonitrile, paraformaldehyde and sodium methoxide in methanol was stirred at 65 °C in for 3 hr until a clear mixture was obtained. The reaction mixture was cooled and sodium borohydride was added slowly and stirred further at room temperature for 1 hr. The crude product was extracted with ethyl acetate and successively washed with water and brine. The ethyl acetate layer was dried with MgSO<sub>4</sub>, and concentrated <i>in vacuo</i>. The crude product was purified on a biotage flash<sup>®</sup> system eluting with 30% ethyl acetate in hexanes containing 0.1 % triethylamine to provide 5-(methylamino)-2-(naphthalen-1-yl)oxazole-4-carbonitrile (<a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a>), a colorless solid end product with 27 % yeild.</div></li></ol></div></div><div id="ml351.s7"><h2 id="_ml351_s7_">3. Results</h2><div id="ml351.s8"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml351.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Dose%20response%20curves%20for%20probe%20ML351%20showing%20inhibition%20of%2015-LOX-1%20in%20the%20UV-Vis%20assay.&p=BOOKS&id=190602_ml351f6.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/NBK190602/bin/ml351f6.jpg" alt="Figure 3. Dose response curves for probe ML351 showing inhibition of 15-LOX-1 in the UV-Vis assay." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">Dose response curves for probe ML351 showing inhibition of 15-LOX-1 in the UV-Vis assay</span></h3></div></div><div id="ml351.s9"><h3>3.2. Cellular Activity</h3><div id="ml351.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20(A)%20Inhibition%20of%2012-HETE%20production%20in%20HT-22%20cells%20by%20ML351%20following%20treatment%20with%20glutamate%20(5%20mM).%20(B)%20Protection%20of%20Glutamate%20(5%20mM)%20induced%20HT-22%20death%20by%20increasing%20amounts%20of%20ML351%20(**%20p%20%3C%200.1%20***%20P%20%3C%200.001).%20Result%20showed%2012%25%20death%20rate%20with%20no%20glutamate%20added%20(normalized%20to%20100%25).&p=BOOKS&id=190602_ml351f7.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/NBK190602/bin/ml351f7.jpg" alt="Figure 4. (A) Inhibition of 12-HETE production in HT-22 cells by ML351 following treatment with glutamate (5 mM). (B) Protection of Glutamate (5 mM) induced HT-22 death by increasing amounts of ML351 (** p < 0.1 *** P < 0.001). Result showed 12% death rate with no glutamate added (normalized to 100%)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">
|
||
(A) Inhibition of 12-HETE production in HT-22 cells by ML351 following treatment with glutamate (5 mM). (B) Protection of Glutamate (5 mM) induced HT-22 death by increasing amounts of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> (** p < 0.1 *** P < 0.001). Result showed 12% death rate with no glutamate added (normalized to 100%).</span></h3></div></div><div id="ml351.s10"><h3>3.3. Profiling Assays</h3><p>Selective profiling of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> and selected analogs showed inactivity of <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> against 15-LOX-2, 12-LOX and 5-LOX, but good inhibition against 15-LOX-1 with 0.02 μM (<a class="figpopup" href="/books/NBK190602/table/ml351.t3/?report=objectonly" target="object" rid-figpopup="figml351t3" rid-ob="figobml351t3">Table 2</a>). Moreover, <a href="/pcsubstance/?term=ML355[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML355</a> represents a vast PK and ADME property improvement over the majority of compounds reported previously (<i>vide infra</i>). Despite the low molecular weight (249 Da), and favorable log D (pH 7.4) of 2.6, most analogs exhibited poor solubility. The aqueous kinetic solubility in PBS buffer was determined to be 1.2 μM, which is about 7 times the <i>in vitro</i> IC<sub>50</sub>. Empirically, a vast improvement in the solubility in the 15-LOX assay buffer was observed which was encouraging and suggests that solubility was not a detrimental factor in the biochemical studies. Importantly, the compound demonstrated favorable PAMPA permeability (passive) and acceptable Caco-2 permeability of >1 (1.5 cm/s<sup>-6</sup>) with no evidence of efflux (efflux ratio: 0.7) suggesting the compound is not susceptible to the action of P-glycoprotein 1 (Pgp), a well-characterized ABC-transporter. Moreover, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> was stable in various aqueous solutions (pH 2, pH 7.4, pH 9) and mouse plasma. In addition, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> exhibited minimal CYP inhibition of the 2D6 and 3A4 isoforms at 10.3% and 3.5% inhibition respectively. Microsomal stability appears to be species dependent with <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> possessing moderate stability to rat liver microsomes (T<sub>1/2</sub> = 18 minutes) while being less stable to mouse liver microsomes (5.5 min). The compounds were completely stable in the absence of NADPH, suggesting a CYP-mediated degradation. Given the interest in testing compound <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> in proof of concept mouse models of stroke, <i>in vivo</i> PK data on <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> was obtained and found a suitable formulation. <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> has a relatively fast half-life in both plasma and brain (T<sub>1/2</sub> = ∼ 1 hr) with a C<sub>max</sub> of 13.8 μM in plasma (69 times <i>in vitro</i> IC<sub>50</sub>) and 28.8 μM in brain (144 times <i>in vitro</i> IC<sub>50</sub>). Encouragingly, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> has a brain/plasma ratio of 2.8 which demonstrates favorable BBB permeability and suggested that this compound was suitable for <i>in vivo</i> proof of concept (POC) models of ischemic stroke (<i>vide infra</i>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml351t3"><a href="/books/NBK190602/table/ml351.t3/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml351t3" rid-ob="figobml351t3"><img class="small-thumb" src="/books/NBK190602/table/ml351.t3/?report=thumb" src-large="/books/NBK190602/table/ml351.t3/?report=previmg" alt="Table 2. Selectivity profiling of ML351 and other top compounds." /></a><div class="icnblk_cntnt"><h4 id="ml351.t3"><a href="/books/NBK190602/table/ml351.t3/?report=objectonly" target="object" rid-ob="figobml351t3">Table 2</a></h4><p class="float-caption no_bottom_margin">Selectivity profiling of ML351 and other top compounds. </p></div></div></div></div><div id="ml351.s11"><h2 id="_ml351_s11_">4. Discussion</h2><div id="ml351.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><div id="ml351.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%205.%20Prior%20Art%20Inhibitors%20of%2015-Lipoxygenase-1%20(15-LOX-1).&p=BOOKS&id=190602_ml351f8.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/NBK190602/bin/ml351f8.jpg" alt="Figure 5. Prior Art Inhibitors of 15-Lipoxygenase-1 (15-LOX-1)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 5</span><span class="title">Prior Art Inhibitors of 15-Lipoxygenase-1 (15-LOX-1)</span></h3></div><p>Previously reported natural product based inhibitors of 15-LOX-1, such as boswellic acid, baicalein [<a class="bk_pop" href="#ml351.r10">10</a>], and nor-dihydroguairetic acid (NDGA) [<a class="bk_pop" href="#ml351.r11">11</a>] all possess several liabilities. These compounds are less potent and less selective towards 15-LOX-1, and are not easily amendable to further optimization as a result of their polyphenolic or terpene-based structures. In comparison, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> is potent (200 nM), selective (no activity against related isozymes or COX-1/2), chemically tractable and drug-like. Our previous chemical probe for 15-LOX-1, <a href="/pcsubstance/?term=ML094[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML094</a>, was found to be extremely potent (14 nM) and selective but lacked activity in cell-based assays, possibly due to poor cell permeability, intracellular hydrolysis of the terminal ester moiety, or inactivity against m12-LOX [<a class="bk_pop" href="#ml351.r12">12</a>]. Tryptamine (<b>37l</b>) and imidazole-based (<b>21n</b>) inhibitors are potent and seemingly selective against 5-LO and 12-LO but a more comprehensive selectivity study is not reported. These compounds were reported to have unfavorable solubility and log P values, and while <b>21n</b> seemed to possess improved physicochemical properties, with a ClogP of >5, there was no <i>in vitro</i> ADME or <i>in vivo</i> PK properties reported. Finally, the pyrazole derivative (<b>15i</b>) has improved solubility and cLogP, as compared to analogs <b>37n</b> and <b>21n</b>, suggesting inconclusive <i>in vivo</i> PK properties so despite the improved properties these compounds remain problematic. Additionally, the compounds reported by the BMS researchers, and in particular <b>21n</b> and <b>15i</b>, are quite complex structurally and possess at least one chiral center which limits their utility as probe compounds unless they are willing to provide academic researcher with the sample. In contrast, <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> has much better ligand efficacy and can be synthesized in 2-3 steps from commercially available starting material. While <a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a> does possess some aforementioned ADME liabilities (solubility, microsomal stability), this report represents the first account of a selective 15-LOX-1 inhibitor with demonstrated BBB permeability and activity in <i>in vivo</i> efficacy models for ischemic stroke.</p><div id="ml351.t4" class="table"><h3><span class="label">Table 3</span><span class="title">Comparison of ML351 to previously identified 15-LOX-1 inhibitors</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK190602/table/ml351.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml351.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12-LOX (IC<sub>50</sub>)</th><th id="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Selective</th><th id="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cell-Active</th><th id="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><i>in vivo</i> efficacy</th></tr></thead><tbody><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b><a href="/pcsubstance/?term=ML351[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML351</a></b></td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">200 nM</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes (HT-22 cells)</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes (stroke)</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Boswelic Acid</b></td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1,000 nM</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>Baicalein</b></td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2,000 nM</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b><a href="/pcsubstance/?term=ML094[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML094</a></b></td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">14 nM</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>NDGA</b></td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">500 nM</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">ND</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“<b>37l</b>”</td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20 nM (rabbit)</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Moderate 5 & 12-LOX</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Unknown</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“<b>21n</b>”</td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">75 nM (rabbit)</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Moderate 5 & 12-LOX</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes (CHO cells)</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Unknown</td></tr><tr><td headers="hd_h_ml351.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">“<b>15i</b>”</td><td headers="hd_h_ml351.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.1 nM (rabbit)</td><td headers="hd_h_ml351.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes, only 12-LOX reported</td><td headers="hd_h_ml351.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes (CHO cells)</td><td headers="hd_h_ml351.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No poor PK</td></tr></tbody></table></div></div></div></div><div id="ml351.s13"><h2 id="_ml351_s13_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml351.r1">Solomon EI, Zhou J, Neese F, Pavel EG. New insights from spectroscopy into the structure/function relationships of lipoxygenases. <span><span class="ref-journal">Chem. Biol. </span>1997;<span class="ref-vol">4</span>:795–808.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9384534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9384534</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml351.r2">Brash AR. Lipoxygenases: Occurrence, Functions, Catalysis and Acquisition of Substrate. <span><span class="ref-journal">J. Biol. Chem. </span>1999;<span class="ref-vol">274</span>:23679–23682.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10446122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10446122</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml351.r3">Berger W, De Chandt MT, Cairns CB. Zileuton: clinical implications of 5-lipoxygenase inhibition in severe airway disease. <span><span class="ref-journal">Int. J. Clin. Pract. </span>2007;<span class="ref-vol">61</span>:663–676.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17394438" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17394438</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml351.r4">Steele VE, Holmes CA, Hawk ET, Kopelovich L, Lubet RA, Crowell JA, Sigman CC, Kelloff GJ. Lipoxygenase inhibitors as potential cancer chemopreventives. <span><span class="ref-journal">Cancer Epidemiol. Biomarkers Prev. </span>1999;<span class="ref-vol">8</span>:467–483.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10350444" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10350444</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml351.r5">Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD. Disruption of the 12/15-lipoxygenase gene diminishes atherosclerosis in apo E–deficient mice. <span><span class="ref-journal">J. Clin. Invest. </span>1999;<span class="ref-vol">103</span>:1597–1604.</span> [<a href="/pmc/articles/PMC408369/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC408369</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10359569" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10359569</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml351.r6">Catalano A, Procopio A. New aspects on the role of lipoxygenases in cancer progression. <span><span class="ref-journal">Histol Histopathol. </span>2005;<span class="ref-vol">20</span>:969–975.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15944947" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15944947</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml351.r7">Harats D, Shaish A, George J, Mulkins M, Kurihara H, Levkovitz H, Sigal E. Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice. <span><span class="ref-journal">Arteriosler. Thromb. Vasc. Biol. </span>2000;<span class="ref-vol">20</span>:2100–2105.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10978255" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10978255</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml351.r8">Setty BN, Werner MH, Hannun YA, Stuart MJ. 15-Hydroxyeicosatetraenoic acid-mediated potentiation of thrombin-induced platelet functions occurs via enhanced production of phosphoinositide-derived second messengers--1,2-diacylglycerol and inositol-1,4,5-trisphosphate. <span><span class="ref-journal">Blood. </span>1992;<span class="ref-vol">80</span>:2765–2773.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1333301" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1333301</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml351.r9">Timár J, Silletti S, Bazaz R, Raz A, Honn KV. Regulation of melanoma-cell motility by the lipoxygenase metabolite 12-(S)-HETE. <span><span class="ref-journal">Int. J. Cancer. </span>1993;<span class="ref-vol">55</span>:1003–1010.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8253518" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8253518</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml351.r10">Svensson H, Grenegard M, Ollinger K, Lindstrom E. Inhibition of 12-lipoxygenase reduces platelet activation and prevents their mitogenic function. <span><span class="ref-journal">Platelets. </span>2013.</span> [Epub ahead of print] [<a href="https://pubmed.ncbi.nlm.nih.gov/23534390" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23534390</span></a>]</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml351.r11">Whitman S, Gezginci M, Timmermann BN, Holman TR. Structure-activity relationship studies of nordihydroguaiaretic acid inhibitors toward soybean, 12-human, and 15-human lipoxygenase. <span><span class="ref-journal">J. Med. Chem. </span>2002;<span class="ref-vol">45</span>:2659–2661.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12036375" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12036375</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml351.r12">Kenyon V, Rai G, Jadhav A, Schultz L, Armstrong M, Jameson BJ, Perry S, Joshi N, Bougie JM, Leister W, Taylor-Fishwick DA, Nadler JL, Holinstat M, Simeonov A, Maloney DJ, Holman TR. Discovery of Potent and Selective Inhibitors of Human Platelet-Type 12-Lipoxygenase. <span><span class="ref-journal">J. Med. Chem. </span>2011;<span class="ref-vol">54</span>:5485–5497.</span> [<a href="/pmc/articles/PMC3150642/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3150642</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21739938" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21739938</span></a>]</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK190602/?report=reader">PubReader</a></li><li><a href="/books/NBK190602/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK190602" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK190602" style="display:none" title="Cite this Page"><div class="bk_tt">Rai G, Joshi N, Perry S, et al. Discovery of ML351, a Potent and Selective Inhibitor of Human 15-Lipoxygenase-1. 2013 Apr 15 [Updated 2014 Jan 13]. 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></div></div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml351.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml351.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml351.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml351.s7" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml351.s11" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml351.s13" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3078796" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=3078796" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3078796" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3078796" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24684213" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.</a><span class="source">[J Med Chem. 2014]</span><div class="brieflinkpop offscreen_noflow">Potent and selective inhibitors of human reticulocyte 12/15-lipoxygenase as anti-stroke therapies.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Rai G, Joshi N, Jung JE, Liu Y, Schultz L, Yasgar A, Perry S, Diaz G, Zhang Q, Kenyon V, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">J Med Chem. 2014 May 22; 57(10):4035-48. 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