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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="A Novel and Selective PAR4 Antagonist: ML354" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2015/02/11" /><meta name="citation_author" content="Summer E. Young" /><meta name="citation_author" content="Matthew T. Duvernay" /><meta name="citation_author" content="Michael L. Schulte" /><meta name="citation_author" content="Kellie D. Nance" /><meta name="citation_author" content="Bruce J. Melancon" /><meta name="citation_author" content="Julie Engers" /><meta name="citation_author" content="Michael R. Wood" /><meta name="citation_author" content="Heidi E. Hamm" /><meta name="citation_author" content="Craig W. Lindsley" /><meta name="citation_pmid" content="25834897" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK280043/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="A Novel and Selective PAR4 Antagonist: ML354" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Summer E. Young" /><meta name="DC.Contributor" content="Matthew T. Duvernay" /><meta name="DC.Contributor" content="Michael L. Schulte" /><meta name="DC.Contributor" content="Kellie D. Nance" /><meta name="DC.Contributor" content="Bruce J. Melancon" /><meta name="DC.Contributor" content="Julie Engers" /><meta name="DC.Contributor" content="Michael R. Wood" /><meta name="DC.Contributor" content="Heidi E. Hamm" /><meta name="DC.Contributor" content="Craig W. Lindsley" /><meta name="DC.Date" content="2015/02/11" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK280043/" /><meta name="description" content="The replacement of a problematic indazole core present in a known class of PAR4 antagonists was successfully implemented through the introduction of an indole core structure. Subsequent libraries of compounds exploring the structure activity relationship (SAR) for this indole series provided PAR4 antagonists with potencies only in the micro-molar range. As a result, a similarity search was conducted which identified 160 candidates from our in-house sample collection for testing against PAR4. From this redirected effort arose ML354, a selective PAR4 antagonist with good potency (PAR4 IC50 = 140 nM), and reasonable selectivity versus PAR1. A lead profiling screen (Pan Labs) identified only 3 potential off-target binding activities, which were all quite weak and unrelated to relevant PAR4 biology. 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From this redirected effort arose ML354, a selective PAR4 antagonist with good potency (PAR4 IC50 = 140 nM), and reasonable selectivity versus PAR1. A lead profiling screen (Pan Labs) identified only 3 potential off-target binding activities, which were all quite weak and unrelated to relevant PAR4 biology. This compound/series also displays improved physical properties and is very amenable to future medicinal chemistry development. Although this molecule contains a nitro group, it still represents the best-in-class PAR4 antagonist for use in vitro, and holds great promise for the development of future in vivo tools." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK280043/" /><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/ml354/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK280043/" /><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="#__NBK280043_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK280043_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/ml355/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml353/" 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="_NBK280043_"><span class="title" itemprop="name">A Novel and Selective PAR4 Antagonist: ML354</span></h1><p class="contrib-group"><span itemprop="author">Summer E. Young</span>, <span itemprop="author">Matthew T. Duvernay</span>, <span itemprop="author">Michael L. Schulte</span>, <span itemprop="author">Kellie D. Nance</span>, <span itemprop="author">Bruce J. Melancon</span>, <span itemprop="author">Julie Engers</span>, <span itemprop="author">Michael R. Wood</span>, <span itemprop="author">Heidi E. Hamm</span>, and <span itemprop="author">Craig W. Lindsley</span>.</p><a data-jig="ncbitoggler" href="#__NBK280043_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK280043_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Summer E. Young</span>,<sup>a</sup> <span itemprop="author">Matthew T. Duvernay</span>,<sup>a</sup> <span itemprop="author">Michael L. Schulte</span>,<sup>b</sup> <span itemprop="author">Kellie D. Nance</span>,<sup>a,c</sup> <span itemprop="author">Bruce J. Melancon</span>,<sup>a,c</sup> <span itemprop="author">Julie Engers</span>,<sup>a,c</sup> <span itemprop="author">Michael R. Wood</span>,<sup>a,c</sup> <span itemprop="author">Heidi E. Hamm</span>,<sup>a</sup> and <span itemprop="author">Craig W. Lindsley</span><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup><sup>a,b,c</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>a</sup>
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Vanderbilt University Medical Center, Nashville, TN 37232, USA<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><div class="affiliation"><sup>b</sup>
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Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><div class="affiliation"><sup>c</sup>
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Vanderbilt Specialized Chemistry Center for Probe Development (MLPCN), Nashville, TN 37232, USA<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><div><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>Corresponding author.</div></div><p class="small">Received: <span itemprop="datePublished">April 15, 2013</span>; Last Update: <span itemprop="dateModified">February 11, 2015</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>The replacement of a problematic indazole core present in a known class of PAR4 antagonists was successfully implemented through the introduction of an indole core structure. Subsequent libraries of compounds exploring the structure activity relationship (SAR) for this indole series provided PAR4 antagonists with potencies only in the micro-molar range. As a result, a similarity search was conducted which identified 160 candidates from our in-house sample collection for testing against PAR4. From this redirected effort arose <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, a selective PAR4 antagonist with good potency (PAR4 IC<sub>50</sub> = 140 nM), and reasonable selectivity versus PAR1. A lead profiling screen (Pan Labs) identified only 3 potential off-target binding activities, which were all quite weak and unrelated to relevant PAR4 biology. This compound/series also displays improved physical properties and is very amenable to future medicinal chemistry development. Although this molecule contains a nitro group, it still represents the best-in-class PAR4 antagonist for use <i>in vitro</i>, and holds great promise for the development of future <i>in vivo</i> tools.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 5P50 HL081009-03</p><p><b>Screening Center Name & PI:</b> N/A – fast track project</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> Heidi E. Hamm, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">652261</a></p><div id="ml354.s1"><h2 id="_ml354_s1_">Probe Structure & Characteristics</h2><div id="ml354.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=ML354.&p=BOOKS&id=280043_ml354f1.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/NBK280043/bin/ml354f1.jpg" alt="ML354." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">ML354</span></h3></div><div id="ml354.t1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280043/table/ml354.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml354.t1_lrgtbl__"><table><thead><tr><th id="hd_h_ml354.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml354.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml354.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml354.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_ml354.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM)<br />[SID, AID]</th><th id="hd_h_ml354.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml354.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name:<br />IC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml354.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 752812/<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a></td><td headers="hd_h_ml354.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PAR4</td><td headers="hd_h_ml354.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">140 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/161003819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161003819</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652253" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652253</a>]</td><td headers="hd_h_ml354.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PAR1</td><td headers="hd_h_ml354.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">∼ 10 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/161003819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161003819</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652255</a>]</td><td headers="hd_h_ml354.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">∼ 71</td><td headers="hd_h_ml354.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Single point PAR4, nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/161003819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161003819</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652250" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652250</a>]</td></tr></tbody></table></div></div></div><div id="ml354.s2"><h2 id="_ml354_s2_">1. Recommendations for Scientific Use of the Probe</h2><div id="ml354.s3"><h3>What limitations in the current state of the art is the probe addressing?</h3><p>Currently, there are no probes available to study the role of PAR4 in thrombosis and hemostasis <i>in vivo</i>. The current PAR4 antagonist YD-3 (1-benzyl-3(ethoxycarbonylphenyl)-indazole) was first described as an antagonist in 2001 and only minimal optimization of this scaffold has occurred since then (see compound 33).<a class="bk_pop" href="#ml354.r1">1</a>,<a class="bk_pop" href="#ml354.r2">2</a> YD-3 has several drawbacks including, a lengthy synthesis route, and its highly lipophilic character, making it unsuitable for rapid chemical optimization and instilling limited <i>in vivo</i> utility. Our understanding of PAR4's role in physiology is similarly limited because of the lack of a sufficient tool compound to selectively study PAR<sub>4</sub>. In order to better understand the role of PAR4 in thrombosis and hemostasis a better PAR4 antagonist has been prepared (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>) which shows reasonable potency (PAR4 IC<sub>50</sub> = 140 nM), acceptable selectivity over PAR1 and a chemical scaffold with improved physical properties that is also much more amenable to further optimization.</p></div><div id="ml354.s4"><h3>How will the probe be used?</h3><p><a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> will allow us to determine basic pharmacological information about PAR4 including receptor density, possible inter-individual variability in PAR4 expression, and mechanism of action of PAR4 antagonists and agonists, data which currently cannot be collected.</p></div><div id="ml354.s5"><h3>Who in the research community will use the probe?</h3><p><a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> will be used by any scientist interested in thrombotic disorders as we know PAR4 plays a major role in stroke, myocardial infarction, thromboembolism, and ischemic diseases.<a class="bk_pop" href="#ml354.r3">3</a> Additionally studies have suggested PAR4 plays a critical role in cancer,<a class="bk_pop" href="#ml354.r4">4</a>,<a class="bk_pop" href="#ml354.r5">5</a> inflammatory disorders such as ulcerative colitis,<a class="bk_pop" href="#ml354.r6">6</a>,<a class="bk_pop" href="#ml354.r7">7</a> and nociception.<a class="bk_pop" href="#ml354.r8">8</a>,<a class="bk_pop" href="#ml354.r9">9</a> This probe could be used by multiple disciplines not only to determine if PAR4 plays a critical role in disease models but also if PAR4 is an acceptable drug target for that disease.</p></div><div id="ml354.s6"><h3>What is the relevant biology to which the probe can be applied?</h3><p>PAR4 probes can be used to study platelet activation, cancer cell proliferation, cellular inflammation, or nociception since PAR4 has been shown to have a role in several physiologic disorders. Further, since mouse PAR4 is highly homologous to human PAR4 the mouse provides a suitable starting point for <i>in vivo</i> investigation of PAR4 in different biological processes.</p></div></div><div id="ml354.s7"><h2 id="_ml354_s7_">2. Materials and Methods</h2><p><b>Platelet Isolation.</b> Platelets were prepared via the standard washed platelet protocol as described below. Briefly, written informed consent was obtained from healthy volunteers in accordance with the Vanderbilt University Internal Review Board approved protocols. Blood drawn into syringes containing 3.2% sodium citrate Platelet rich plasma was prepared by centrifugation at 170g for 15 minutes. 10× acid citrate dextrose was added to platelet rich plasma and centrifuged at 800g for 10 minutes at room temperature. The supernatant was aspirated and the platelet pellet was suspended in Tyrode's buffer (15 mM HEPES, 0.33 mM NaH2PO4 (pH 7.4), 138 mM NaCl, 2.7 mM KCl, 1 mM MgCl2, 5.5 mM dextrose) containing 0.1% Bovine Serum Albumin fraction V (BSA) and counted on a Beckman Z1 Coulter particle counter (Brea, CA).</p><p><b>Calcium Mobilization Assays – Single Point Screening.</b> Washed human platelets were prepared via the standard procedure (vide supra) and suspended in Tyrode's buffer containing 0.1% BSA. Platelets were dye loaded for 1 hour with Fluo4-AM (Invitrogen, Eugene, OR) in calcium assay buffer (1× HBSS, 20 mM HEPES, 2.5 mM probenecid without calcium or magnesium). The calcium assay buffer containing dye was mixed with platelets to yield a final concentration of 2.5 μg/mL Fluo4-AM and 1.0×10<sup>8</sup> platelets/mL. 60 μL of dye loaded platelets were added to each well of a NUNC 384 well plate black optical bottom plate (Thermo, Rochester, NY). Fluorescence measurements were recorded in the Vanderbilt Center for Neuroscience Drug Discovery's Screening Center using a Functional Drug Screening System 6000, Hamamatsu (Hamamatsu, Japan). 10 μM of each compound was added in triplicate 6 minutes prior to the addition of 80 μM Protease activated receptor 4-activating peptide (PAR4-AP) (GL Biochem, Shanghai, China). 480:540 (ex:em) was measured each second for a total of 12 minutes at 37 °C. The final concentration of DMSO in the assay was 0.5%. The difference between basal and maximal relative fluorescence unit values (RFUs) for ex:em 480:540 was determined for each well. The change in RFU for DMSO treated control stimulated with 80 μM PAR4-AP was set to 100% for each donor. IC<sub>50</sub> values were determined using GraphPad PRISM v.5.0 inhibitory sigmoidal dose response ‘variable slope’ parameter.</p><p><b>PAC-1 Binding – Potency and Selectivity.</b> Briefly, 60 μL of washed platelets (Tyrodes buffer containing 0.1% BSA) at a concentration of 0.15 ×10<sup>8</sup> platelets/mL were added to 5 mL round bottom polystyrene tubes (BD, Franklin Lakes, NJ). FITC conjugated PAC-1 (BD Biosciences, San Jose, CA) antibody was diluted (to the manufacturers recommended concentration) in Tyrode's buffer containing 0.1% BSA. 40 μL of diluted antibody was added to the platelets and allowed to bind for 5 minutes. Platelets were pre-treated with indicated concentrations of antagonist or DMSO control for 5 minutes followed by addition of PAR1-AP (GL Biochem, Shanghai, China) or PAR4-AP for 10 minutes. Platelet activity was quenched by the addition ice cold 1.5% paraformaldehyde followed by dilution in 1× phosphate buffered saline. The final DMSO concentration was 0.5%. Platelets were stored up to 18 hours at 4 °C before flow cytometric analysis. Analysis was carried out on a BD FACS Canto II (Franklin Lakes, NJ). Fluorescent intensity was determined for 100,000 events within the platelet gate. Data was collected and analyzed via FACS DiVa software. Flow cytometric data analysis was conducted by the following method. 100% response for PAR4-AP was determined for each individual as the DMSO treated control stimulated with either 200 μM PAR4-AP, or 20 μM PAR1-AP. Data was plotted in GraphPad PRISM v.5.0. Dose response curves and subsequent IC<sub>50</sub> values were generated using the inhibitory sigmoidal dose response ‘variable slope’ parameter. PAR4 results were plotted is mean ± SEM. Compounds displaying IC<sub>50</sub>'s less than 1 μM were assigned ‘Outcome’ = Active, and subject to PAR1 PAC1 selectivity screens.</p><div id="ml354.s8"><h3>2.1. Assays</h3><dl class="temp-labeled-list"><dt>2.1.1.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652261" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652261</a> (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> Discovery of Novel Antagonists of Protease activated receptor 4 - BioAssay Summary)</p></dd><dt>2.1.2.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652250" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652250</a> (Discovery of Novel Antagonists of Protease activated receptor 4: Single Point)</p></dd><dt>2.1.3.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652255" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652255</a> (Discovery of Novel Antagonists of Protease activated receptor 4: PAR 1 Selectivity CRC Assay)</p></dd><dt>2.1.4.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/652253" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 652253</a> (Discovery of Novel Antagonists of Protease activated receptor 4: CRC Assay)</p></dd><dt>2.1.5.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686926" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686926</a> (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> Eurofin Panel Assay for PAR4 Antagonists Inhibitor (Probe Compound))</p></dd></dl></div><div id="ml354.s9"><h3>2.2. Probe Chemical Characterization</h3><div id="ml354.f3" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml354f3&p=BOOKS&id=280043_ml354f3.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/NBK280043/bin/ml354f3.jpg" alt="Image ml354f3" class="tileshop" title="Click on image to zoom" /></a></div></div><p>Probe compound <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> (CID 752812, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161003819" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161003819</a>, VU0099704) could be prepared according to the above route, but was most efficiently obtained from commercial sources and provided the following characterization. <b>(1-methyl-5-nitro-3-phenyl-1H-indol-2-yl)methanol:</b>
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<sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ (ppm): 8.58 (d, <i>J</i> = 2.1 Hz, 1H); 8.17 (dd, <i>J</i><sub>1</sub> = 9.1 Hz, <i>J</i><sub>2</sub> = 2.2 Hz, 1H); 7.55-7.49 (m, 2H); 7.48-7.36 (m, 4H); 4.90 (s, 2H); 3.97 (s, 3H). <sup>13</sup>C NMR (100 MHz, CDCl<sub>3</sub>) δ (ppm): 142.11; 140.07; 137.73; 133.03; 130.00; 129.14; 127.52; 126.06; 119.46; 118.42; 117.61; 109.37; 55.08; 30.80. HRMS (TOF, ES<sup>+</sup>) for C<sub>16</sub>H<sub>14</sub>N<sub>2</sub>O<sub>3</sub> [M+Na<sup>+</sup>] calc. mass: 283.1083; found: 283.1081.</p><p><b>Solubility:</b> Solubility for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> in PBS (@ pH = 7.4, final DMSO concentration 1%) was determined to be 3.3 ± 0.5 μM, which is 26-fold higher than its PAR4 IC<sub>50</sub>.</p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> at 23 °C in PBS (no antioxidants or other protectorants, initial <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> concentration = 10 μM and final DMSO concentration 10%). After 48 hours, 94.5% of the initial concentration of <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> remained. There was no significant change in concentration between the 24 and 48 hour time points indicating that <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> is very stable in solution under these conditions and may even be stable for longer periods of time in solution.</p><div id="ml354.t2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280043/table/ml354.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml354.t2_lrgtbl__"><table><thead><tr><th id="hd_h_ml354.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th id="hd_h_ml354.t2_1_1_1_2" colspan="6" rowspan="1" style="text-align:center;vertical-align:top;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml354.t2_1_1_1_1" id="hd_h_ml354.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0 min</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19 min</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">37 min</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90 min</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24 hr</th><th headers="hd_h_ml354.t2_1_1_1_2" id="hd_h_ml354.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48 hr</th></tr></thead><tbody><tr><td headers="hd_h_ml354.t2_1_1_1_1 hd_h_ml354.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, CID 752812</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">97.6</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">98.8</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">96.9</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">94.2</td><td headers="hd_h_ml354.t2_1_1_1_2 hd_h_ml354.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">94.5</td></tr></tbody></table></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS004820369 (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, CID 752812, 25.0 mg); MLS004820370 (CID 71148622, 17.0 mg); MLS004820371 (CID 71148620, 15.8 mg); MLS004820372 (CID 71148614, 6.2 mg); MLS004820373 (CID 71148612, 17.7 mg); MLS004820374 (CID 71148613, 5.0 mg)</p></div><div id="ml354.s10"><h3>2.3. Probe Preparation</h3><p>The chemical structure and method of preparation for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> has been know since 1983.<a class="bk_pop" href="#ml354.r14">14</a> Presumably, this original Fischer indole synthesis route is still the method used for its commercial preparation. Unfortunately, the first step in this published sequence calls for the condensation of (4-nitrophenyl)hydrazine and phenylacetone. Although this chemistry is well precedented, phenylacetone is a Schedule II controlled substance due to its obvious relationship to methamphetamine. Wishing to avoid the regulatory procedures associated with using phenylacetone, and in an effort to apply more recent and potentially more flexible chemistry toward the preparation of <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, we initiated the synthesis route depicted in <a href="#ml354.s9">Section 2.2</a>. While the chemical transformations comprising this new route are all well precedented, its optimization and actual execution is still ongoing at the time of this probe report. Once optimization is complete, this new route will allow for the rapid preparation of diverse analogs of the PAR4 antagonist <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, and will be reported in due course.</p></div></div><div id="ml354.s11"><h2 id="_ml354_s11_">3. Results</h2><p>Published preparations for the known PAR4 antagonists, YD-3<a class="bk_pop" href="#ml354.r1">1</a> and related analogs,<a class="bk_pop" href="#ml354.r2">2</a> entail 9-step routes with complex mixtures of <i>N</i>-1 and <i>N</i>-2 indazole benzylation products. Using YD-3 as a starting point, we first sought to prepare analogs which possessed a simplified core and a higher-yielding synthesis route. <a class="figpopup" href="/books/NBK280043/figure/ml354.f4/?report=objectonly" target="object" rid-figpopup="figml354f4" rid-ob="figobml354f4">Figure 2</a> shows YD-3 and two early attempts at replacing the indazole core. It should be pointed out that the differences in potency for YD-3 appearing in <a class="figpopup" href="/books/NBK280043/figure/ml354.f2/?report=objectonly" target="object" rid-figpopup="figml354f2" rid-ob="figobml354f2">Figures 1</a> and <a class="figpopup" href="/books/NBK280043/figure/ml354.f4/?report=objectonly" target="object" rid-figpopup="figml354f4" rid-ob="figobml354f4">2</a> are a result of the different assays used to assess PAR4 inhibition. Although introduction of the hydroxyl indolinone core, in MLS-E-6, resulted in an inactive compound, the indole substitution provided a compound with nanomolar potency (PAR4 IC<sub>50</sub> = 66 nM). Observing only a 2.5-fold decrease in potency for EBIB relative to YD-3 clearly validated the indole core as an attractive replacement for the indazole. Furthermore, these new analogues could be prepared via the highly efficient, 3-step route generally depicted in <a class="figpopup" href="/books/NBK280043/figure/ml354.f5/?report=objectonly" target="object" rid-figpopup="figml354f5" rid-ob="figobml354f5">Scheme 1</a>. Briefly, substituted indoles can be <i>N</i>-benzylated with benzyl halides and sodium hydride, followed by NBS bromination at the 3-position of the indole. These indole bromides can then undergo efficient palladium(0) catalyzed coupling with a large variety of boronic acids/esters to provide a diverse range of substituted indole PAR4 antagonist.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f4" co-legend-rid="figlgndml354f4"><a href="/books/NBK280043/figure/ml354.f4/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml354f4" rid-ob="figobml354f4"><img class="small-thumb" src="/books/NBK280043/bin/ml354f4.gif" src-large="/books/NBK280043/bin/ml354f4.jpg" alt="Figure 2. Replacements for the indazole core of YD-3." /></a><div class="icnblk_cntnt" id="figlgndml354f4"><h4 id="ml354.f4"><a href="/books/NBK280043/figure/ml354.f4/?report=objectonly" target="object" rid-ob="figobml354f4">Figure 2</a></h4><p class="float-caption no_bottom_margin">Replacements for the indazole core of YD-3. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f2" co-legend-rid="figlgndml354f2"><a href="/books/NBK280043/figure/ml354.f2/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml354f2" rid-ob="figobml354f2"><img class="small-thumb" src="/books/NBK280043/bin/ml354f2.gif" src-large="/books/NBK280043/bin/ml354f2.jpg" alt="Figure 1. Known PAR4 antagonists." /></a><div class="icnblk_cntnt" id="figlgndml354f2"><h4 id="ml354.f2"><a href="/books/NBK280043/figure/ml354.f2/?report=objectonly" target="object" rid-ob="figobml354f2">Figure 1</a></h4><p class="float-caption no_bottom_margin">Known PAR4 antagonists. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f5" co-legend-rid="figlgndml354f5"><a href="/books/NBK280043/figure/ml354.f5/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml354f5" rid-ob="figobml354f5"><img class="small-thumb" src="/books/NBK280043/bin/ml354f5.gif" src-large="/books/NBK280043/bin/ml354f5.jpg" alt="Scheme 1. Generalized preparation for the compounds appearing in Tables 1 and 2." /></a><div class="icnblk_cntnt" id="figlgndml354f5"><h4 id="ml354.f5"><a href="/books/NBK280043/figure/ml354.f5/?report=objectonly" target="object" rid-ob="figobml354f5">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Generalized preparation for the compounds appearing in Tables 1 and 2. </p></div></div><p>These successful initial results and the simplified preparation of this novel class of PAR4 antagonists enabled the submission, and acceptance, of an MLPCN Fast Track application. Looking to improve the physical properties and metabolic stability of EBIB our next goal was to replace the ethyl ester, which represented a potential metabolic liability, and introduce polarity or weakly basic amines. Towards this goal, libraries were produced which explored alternative Ar<sup>2</sup> groups, as depicted in <a class="figpopup" href="/books/NBK280043/figure/ml354.f5/?report=objectonly" target="object" rid-figpopup="figml354f5" rid-ob="figobml354f5">Scheme 1</a>. <a class="figpopup" href="/books/NBK280043/table/ml354.t3/?report=objectonly" target="object" rid-figpopup="figml354t3" rid-ob="figobml354t3">Table 1</a> lists some of the more interesting structures which were initially tested in a single point screen, at 10 μM, to quickly obtain an idea of their ability to inhibit PAR4. The data appearing in the right-most column represents PAR4 activity remaining, relative to a DMSO control. Replacing the ethyl ester with a methyl ether, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145949" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145949</a>, provided a compound which inhibited PAR4 activity down to 27%, a very encouraging result among our initial libraries. Ethers with larger alkyl groups (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870441" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SIDs 160870441</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870439" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">160870439</a>), more electron withdrawing ethers (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870442" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160870442</a>), or ethers in the <i>meta</i> positions (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145950" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145950</a>) did not show improved inhibition. Moving away from substituted phenyls, a pyrazole (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145945" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145945</a>) and pyrimidine analogues (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870438" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160870438</a>, etc.) did not show improved activity over the 4-OMe phenyl compound. However, the pyrimidines suggested that 3-pyridyl should be explored. With the exception of the 4-pyridyl analog <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145951" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145951</a>, the mono- and di-substituted 3-pyridyl compounds all displayed some level of PAR4 antagonism. The most encouraging compounds were <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145947" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145947</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145946" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145946</a>, with just 28% and 17% activity remaining when tested at 10 μM. Those PAR4 antagonists showing less than 30% activity remaining (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145949" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145949</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145947" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145947</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145946" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145946</a>) were further characterized in a related concentration response experiment to determine their IC<sub>50</sub>s for PAR4. Quite disappointingly, the first two failed to return a measurable IC<sub>50</sub> (> 10 μM), while <a href="https://pubchem.ncbi.nlm.nih.gov/substance/152145946" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 152145946</a> yielded a PAR4 IC<sub>50</sub> of only 5.4 μM. Although this did represent an approximately 80-fold decrease in potency relative to EBIB, we felt that replacing the ethyl benzoate with a 6-MeO-pyridin-3-yl heterocycle was a reasonable trade off.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml354t3"><a href="/books/NBK280043/table/ml354.t3/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml354t3" rid-ob="figobml354t3"><img class="small-thumb" src="/books/NBK280043/table/ml354.t3/?report=thumb" src-large="/books/NBK280043/table/ml354.t3/?report=previmg" alt="Table 1. Indole PAR4 antagonists." /></a><div class="icnblk_cntnt"><h4 id="ml354.t3"><a href="/books/NBK280043/table/ml354.t3/?report=objectonly" target="object" rid-ob="figobml354t3">Table 1</a></h4><p class="float-caption no_bottom_margin">Indole PAR4 antagonists. </p></div></div><p>We next held the top aryl group constant, as the 6-MeO-pyridin-3-yl, while we attempted to improve potency through modifications of the <i>N</i>-benzyl group. <a class="figpopup" href="/books/NBK280043/table/ml354.t4/?report=objectonly" target="object" rid-figpopup="figml354t4" rid-ob="figobml354t4">Table 2</a> highlights only the most successful analogues from this endeavor, along with their single point screening values and the subsequently obtained PAR4 IC<sub>50</sub>s. Consistent with previous SAR developed around the indazole series of PAR4 antagonists,<a class="bk_pop" href="#ml354.r2">2</a>
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||
<i>meta</i>-substituents provided the best results in these indole analogues. Of the halogenated analogues, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160870425</a> displayed the best IC<sub>50</sub> of 3.1 μM. More polar substituents which showed promising results in the single-point screen (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870449" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160870449</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/160870443" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 160870443</a>) both possessed IC<sub>50</sub> values > 10 μM, despite showing encouraging levels of antagonism in the single point screen (14% and 24% respectively).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml354t4"><a href="/books/NBK280043/table/ml354.t4/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml354t4" rid-ob="figobml354t4"><img class="small-thumb" src="/books/NBK280043/table/ml354.t4/?report=thumb" src-large="/books/NBK280043/table/ml354.t4/?report=previmg" alt="Table 2. Indole PAR4 antagonists with m-Substituents." /></a><div class="icnblk_cntnt"><h4 id="ml354.t4"><a href="/books/NBK280043/table/ml354.t4/?report=objectonly" target="object" rid-ob="figobml354t4">Table 2</a></h4><p class="float-caption no_bottom_margin">Indole PAR4 antagonists with <i>m</i>-Substituents. </p></div></div><p>Beginning to realize that we might not be able to obtain reasonable potencies for this indole class of compounds without including the ethyl benzoate present in YD-3 and EBIB (<a class="figpopup" href="/books/NBK280043/figure/ml354.f4/?report=objectonly" target="object" rid-figpopup="figml354f4" rid-ob="figobml354f4">Figure 2</a>), we conducted a rudimentary structural similarity search around the lead indole. We selected compounds which were somewhat similar to EBIB <u>and</u> which were readily available within Vanderbilt's sample repository. Approximately 160 compounds were selected for single point testing, and <a class="figpopup" href="/books/NBK280043/figure/ml354.f6/?report=objectonly" target="object" rid-figpopup="figml354f6" rid-ob="figobml354f6">Figure 3</a> illustrates some of the structural diversity which was explored. Four ‘actives’ were obtained from this similarity screen (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/161004578" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161004578</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161004613" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161004613</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161004645" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161004645</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161004647" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161004647</a>). Among these four, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161004645" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161004645</a> (CID 752812) proved to be the most attractive hit despite the presence of an aryl nitro group. We consulted with the assay provider and decided that since the use of this compound would most likely be limited to <i>in vitro</i> experiments with isolated platelets, the presence of a nitro group was of limited concern. That being said, we believe it would still be advantageous to explore molecules which do not contain such a potentially offensive moiety. One distinct advantage of this new lead was its commercial availability, both with an eye towards activity confirmation and subsequent derivatization. As such, we promptly ordered a gram of CID 752812 (Chembridge# 5280909) and set about characterizing its structure and confirming its activity. The spectral data appearing in <a href="#ml354.s9">Section 2.2</a> reliably confirmed its structure and we were very pleased to determine its PAR4 antagonist IC<sub>50</sub> = 140 nM! Simultaneously we explored a small subset of the readily accessible analogues shown in <a class="figpopup" href="/books/NBK280043/figure/ml354.f7/?report=objectonly" target="object" rid-figpopup="figml354f7" rid-ob="figobml354f7">Figure 4</a>. Direct alkylation of the hydroxyl provided ether analogues of varing activity, the best of which was a sub-nanomolar compound against PAR4, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/161780288" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 161780288</a>. Oxidation of the alcohol to an aldehyde could be followed by reductive aminations or Grignard additions under standard conditions to provide amines and secondary alcohols, respectively. However, neither of these latter two approaches provided any improvement over CID 752812. In fact, of the three classes of derivatives prepared around CID 752812, none has yet to provide an improvement in potency relative to CID 752812 (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>). These results thus far would suggest that SAR around this indole series of PAR4 antagonists is fairly steep. However, given the low molecular weight for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> (MW = 282), its commercial availability and its easy-to-derivatize structure, we are confident that future work will result in further improvements in PAR4 potency and are optimistic with regard to replacing, or removing, the nitro functionality.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f6" co-legend-rid="figlgndml354f6"><a href="/books/NBK280043/figure/ml354.f6/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml354f6" rid-ob="figobml354f6"><img class="small-thumb" src="/books/NBK280043/bin/ml354f6.gif" src-large="/books/NBK280043/bin/ml354f6.jpg" alt="Figure 3. Sampling of the diversity explored around the lead compound EBIB, as obtained from a structural similarity search." /></a><div class="icnblk_cntnt" id="figlgndml354f6"><h4 id="ml354.f6"><a href="/books/NBK280043/figure/ml354.f6/?report=objectonly" target="object" rid-ob="figobml354f6">Figure 3</a></h4><p class="float-caption no_bottom_margin">Sampling of the diversity explored around the lead compound EBIB, as obtained from a structural similarity search. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f7" co-legend-rid="figlgndml354f7"><a href="/books/NBK280043/figure/ml354.f7/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml354f7" rid-ob="figobml354f7"><img class="small-thumb" src="/books/NBK280043/bin/ml354f7.gif" src-large="/books/NBK280043/bin/ml354f7.jpg" alt="Figure 4. Derivatives of CID 75812 (ML354)." /></a><div class="icnblk_cntnt" id="figlgndml354f7"><h4 id="ml354.f7"><a href="/books/NBK280043/figure/ml354.f7/?report=objectonly" target="object" rid-ob="figobml354f7">Figure 4</a></h4><p class="float-caption no_bottom_margin">Derivatives of CID 75812 (ML354). </p></div></div><p>Since only PAR1 and PAR4 are expressed on platelets, we determined <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>'s IC<sub>50</sub> against PAR1 and were encouraged to measure a PAR1 IC<sub>50</sub> ∼ 10 μM, indicating a roughly 70-fold selectivity for PAR4 over PAR1 (<a class="figpopup" href="/books/NBK280043/figure/ml354.f8/?report=objectonly" target="object" rid-figpopup="figml354f8" rid-ob="figobml354f8">Figure 5</a>). In summary, <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> represents a very attractive probe compound for the <u><i>in vitro</i></u> study of platelet activation and will likely represent a critical starting point for the future development of a highly selective <i>in vivo</i> tool compound. An additional advantage of <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> is its commercial availability, rendering it readily and immediately available to the broader scientific community.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml354f8" co-legend-rid="figlgndml354f8"><a href="/books/NBK280043/figure/ml354.f8/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml354f8" rid-ob="figobml354f8"><img class="small-thumb" src="/books/NBK280043/bin/ml354f8.gif" src-large="/books/NBK280043/bin/ml354f8.jpg" alt="Figure 5. PAR4 and PAR1 CRC for ML354 (VU0099704)." /></a><div class="icnblk_cntnt" id="figlgndml354f8"><h4 id="ml354.f8"><a href="/books/NBK280043/figure/ml354.f8/?report=objectonly" target="object" rid-ob="figobml354f8">Figure 5</a></h4><p class="float-caption no_bottom_margin">PAR4 and PAR1 CRC for ML354 (VU0099704). </p></div></div><div id="ml354.s12"><h3>3.1. Dose Response Curves for Probe</h3><p>See <a class="figpopup" href="/books/NBK280043/figure/ml354.f8/?report=objectonly" target="object" rid-figpopup="figml354f8" rid-ob="figobml354f8">Figure 5</a> (<i>vide supra</i>) for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>'s antagonist activity determinations against PAR1 and PAR4.</p></div><div id="ml354.s13"><h3>3.2. Cellular Activity</h3><p>In the most rigorous sense, cellular activity has not been accessed for these PAR4 antagonists because their site of action occurs at the PAR4 receptor located on platelets. Assays preformed during the development of <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> were all conducted on freshly collected and isolated human platelets, which are not considered cells.</p></div><div id="ml354.s14"><h3>3.3. Profiling Assays</h3><p>To more fully characterize <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, and to better inform the scientific community about its potential off target activities, this 1<sup>st</sup> generation PAR4 antagonist was tested using Eurofins' (formerly Ricerca's, formerly MDS Pharma's) Pan Labs Lead Profiling Screen (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/686926" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 686926</a>). This battery of radioligand binding assays consists of 68 common GPCRs, ion channels and transporters where the test compound (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>) was present at 10 μM. Responses were considered significant if > 50% inhibition was observed. However it should be pointed out that these are only single-point values and that functional selectivity may be significantly better than suggested by these “% inhibitions.” <a class="figpopup" href="/books/NBK280043/table/ml354.t5/?report=objectonly" target="object" rid-figpopup="figml354t5" rid-ob="figobml354t5">Table 3</a> presents the Pan Labs results for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, which showed a significant response in only three assays. Importantly, none of these alleged activities would be expected to participate in the coagulation cascade, or be present on human platelets, indicating that studies performed with isolated human platelets and <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> are highly focused towards PAR4 effects.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml354t5"><a href="/books/NBK280043/table/ml354.t5/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml354t5" rid-ob="figobml354t5"><img class="small-thumb" src="/books/NBK280043/table/ml354.t5/?report=thumb" src-large="/books/NBK280043/table/ml354.t5/?report=previmg" alt="Table 3. Pan Labs profiling of ML354." /></a><div class="icnblk_cntnt"><h4 id="ml354.t5"><a href="/books/NBK280043/table/ml354.t5/?report=objectonly" target="object" rid-ob="figobml354t5">Table 3</a></h4><p class="float-caption no_bottom_margin">Pan Labs profiling of ML354. </p></div></div><p>Additionally, a set of calculated physical properties were determined for <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> and compared to the averaged values for compounds appearing in the MDDR database (MDL Drug Data Report database, 2010) at two stages of clinical development (Phase I and Launched, <a class="figpopup" href="/books/NBK280043/table/ml354.t6/?report=objectonly" target="object" rid-figpopup="figml354t6" rid-ob="figobml354t6">Table 4</a>). <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> compares favorably with the average values for both Phase I and Launched compounds. The most notable departure from this favorable comparison occurs in the comparison of cLogP values, and although <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> is on the high side of the MDDR ranges, it is still a substantial improvement over the cLogP value for the lead compound YD-3 (cLogP = 5.4).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml354t6"><a href="/books/NBK280043/table/ml354.t6/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml354t6" rid-ob="figobml354t6"><img class="small-thumb" src="/books/NBK280043/table/ml354.t6/?report=thumb" src-large="/books/NBK280043/table/ml354.t6/?report=previmg" alt="Table 4. Calculated property comparison between the PAR4 probe and MDDR compounds." /></a><div class="icnblk_cntnt"><h4 id="ml354.t6"><a href="/books/NBK280043/table/ml354.t6/?report=objectonly" target="object" rid-ob="figobml354t6">Table 4</a></h4><p class="float-caption no_bottom_margin">Calculated property comparison between the PAR4 probe and MDDR compounds. </p></div></div></div></div><div id="ml354.s15"><h2 id="_ml354_s15_">4. Discussion</h2><div id="ml354.s16"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Presently, there are no PAR4 tool compounds available for <i>in vivo</i> experiments exploring thrombosis and hemostasis, and although this probe (<a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>) does not meet this formidable goal, it is clearly a step in the right direction. Relative to the only known, small molecule PAR4 antagonists, which are all indazoles (<i>e.g.</i>, YD-3 and ‘compound 33’, <a class="figpopup" href="/books/NBK280043/figure/ml354.f2/?report=objectonly" target="object" rid-figpopup="figml354f2" rid-ob="figobml354f2">Figure 1</a>), <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> possesses a number of improvements. Although a slight decrease in potency was engendered with <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a>, its improvements in cLogP, lower molecular weight, ease of preparation and chemical tractability clearly support <a href="/pcsubstance/?term=ML354[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML354</a> as the best in class PAR4 antagonist for use as an <i>in vitro</i> tool compound. Furthermore, the full SAR surrounding this new lead structure can be efficiently explored and will likely result in PAR4 antagonists with additional improvements. These improvements will better position future compounds to be used as <i>in vivo</i> tools to validate the role and promise of PAR4 antagonists in the treatment of thrombotic and inflammatory disorders.</p></div></div><div id="ml354.s17"><h2 id="_ml354_s17_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml354.r1">Lee F, et al. Synthesis of 1-benzyl-3-(5′-hydroxymethyl-2′-furyl)indazole analogues as novel antiplatelet agents. <span><span class="ref-journal">Journal of medicinal chemistry. </span>2001;<span class="ref-vol">44</span>:3746–3755.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11606139" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11606139</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml354.r2">Chen H-S, et al. Synthesis and antiplatelet activity of ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) derivatives. <span><span class="ref-journal">Bioorganic & medicinal chemistry. </span>2008;<span class="ref-vol">16</span>:1262–1340.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17988878" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17988878</span></a>] [<a href="http://dx.crossref.org/10.1016/j.bmc.2007.10.070" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml354.r3">Hamilton J, Cornelissen I, Coughlin S. Impaired hemostasis and protection against thrombosis in protease-activated receptor 4-deficient mice is due to lack of thrombin signaling in platelets. <span><span class="ref-journal">Journal of thrombosis and haemostasis : JTH. </span>2004;<span class="ref-vol">2</span>:1429–1464.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15304051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15304051</span></a>] [<a href="http://dx.crossref.org/10.1111/j.1538-7836.2004.00783.x" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml354.r4">Kaufmann R, et al. Thrombin-mediated hepatocellular carcinoma cell migration: cooperative action via proteinase-activated receptors 1 and 4. <span><span class="ref-journal">Journal of cellular physiology. </span>2007;<span class="ref-vol">211</span>:699–1406.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17323377" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17323377</span></a>] [<a href="http://dx.crossref.org/10.1002/jcp.21027" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml354.r5">Black P, et al. Overexpression of protease-activated receptors-1,-2, and-4 (PAR-1, -2, and -4) in prostate cancer. <span><span class="ref-journal">The Prostate. </span>2007;<span class="ref-vol">67</span>:743–799.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17373694" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17373694</span></a>] [<a href="http://dx.crossref.org/10.1002/pros.20503" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml354.r6">Braga A, et al. Blockade of proteinase-activated receptor-4 inhibits the eosinophil recruitment induced by eotaxin-1 in the pleural cavity of mice. <span><span class="ref-journal">Pharmacology. </span>2010;<span class="ref-vol">86</span>:224–254.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20829647" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20829647</span></a>] [<a href="http://dx.crossref.org/10.1159/000319751" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml354.r7">Dabek M, et al. Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. <span><span class="ref-journal">The American journal of pathology. </span>2009;<span class="ref-vol">175</span>:207–221.</span> [<a href="/pmc/articles/PMC2708807/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2708807</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19528350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19528350</span></a>] [<a href="http://dx.crossref.org/10.2353/ajpath.2009.080986" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml354.r8">Asfaha S, et al. Protease-activated receptor-4: a novel mechanism of inflammatory pain modulation. <span><span class="ref-journal">British journal of pharmacology. </span>2007;<span class="ref-vol">150</span>:176–261.</span> [<a href="/pmc/articles/PMC2042908/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2042908</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17179954" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17179954</span></a>] [<a href="http://dx.crossref.org/10.1038/sj.bjp.0706975" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml354.r9">Russell F, Veldhoen V, Tchitchkan D, McDougall J. Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism. <span><span class="ref-journal">Journal of neurophysiology. </span>2010;<span class="ref-vol">103</span>:155–218.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19889854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19889854</span></a>] [<a href="http://dx.crossref.org/10.1152/jn.00486.2009" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml354.r10">For
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a review of the PAR family of receptors see:
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<span class="element-citation" id="ec1">Adams MN, et al. Structure, function and pathophysiology of protease activated receptors. <span><span class="ref-journal">Pharmacology & Therapeutics. </span>2011;<span class="ref-vol">130</span>:248–282.</span> [<a href="//doi.org/10.1016%2Fj.pharmthera.2011.01.003" target="_blank" rel="noopener noreferrer">CrossRef</a>] <span class="nowrap">[<a href="https://scholar.google.com/scholar_lookup?journal=Pharmacology+&+Therapeutics&title=Structure,+function+and+pathophysiology+of+protease+activated+receptors&author=MN+Adams&volume=130&publication_year=2011&pages=248-282&pmid=21277892&doi=10.1016/j.pharmthera.2011.01.003&" target="_blank" rel="noopener noreferrer">Google Scholar</a>]</span></span></div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml354.r11">Morrow DA, et al. Vorapaxar in the secondary prevention of atherothrombotic events. <span><span class="ref-journal">New England Journal of Medicine. </span>2012;<span class="ref-vol">366</span>:1404–1413.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22443427" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22443427</span></a>] [<a href="http://dx.crossref.org/10.1056/NEJMoa1200933" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml354.r12">Tricoci P, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. <span><span class="ref-journal">New England Journal of Medicine. </span>2012;<span class="ref-vol">366</span>:20–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22077816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22077816</span></a>] [<a href="http://dx.crossref.org/10.1056/NEJMoa1109719" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml354.r13">Duvernay M, et al. Protease-activated receptor (PAR) 1 and PAR4 differentially regulate factor V expression from human platelets. <span><span class="ref-journal">Molecular pharmacology. </span>2013;<span class="ref-vol">83</span>:781–792.</span> [<a href="/pmc/articles/PMC3608438/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3608438</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23307185" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23307185</span></a>] [<a href="http://dx.crossref.org/10.1124/mol.112.083477" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">CrossRef</a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ml354.r14">Krichevskii ES, et al. New approach to the synthesis of 2-aminomethyl-3-phenyl-5-nitroindole derivatives. <span><span class="ref-journal">Khimiya Geterotsiklicheskikh Soedinenii. </span>1983;<span class="ref-vol">12</span>:1648–1651.</span> doi:NA, Russian.</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/NBK280043/?report=reader">PubReader</a></li><li><a href="/books/NBK280043/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK280043" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK280043" style="display:none" title="Cite this Page"><div class="bk_tt">Young SE, Duvernay MT, Schulte ML, et al. A Novel and Selective PAR4 Antagonist: ML354. 2013 Apr 15 [Updated 2015 Feb 11]. 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="#ml354.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml354.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml354.s7" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml354.s11" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml354.s15" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml354.s17" ref="log$=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=3412210" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3412210" ref="log$=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=3412210" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/27318768" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Differential anti-thrombotic benefit and bleeding risk profiles of antagonists of protease-activated receptor 1 and 4 in Cynomolgus Macaques.</a><span class="source">[Thromb Res. 2016]</span><div class="brieflinkpop offscreen_noflow">Differential anti-thrombotic benefit and bleeding risk profiles of antagonists of protease-activated receptor 1 and 4 in Cynomolgus Macaques.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wickham LA, Sitko G, Stranieri-Michener M, Handt L, Basso A, Fried S, Chu L, Maderia M, Owens K, Castriota G, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Thromb Res. 2016 Sep; 145:133-9. 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