Louise Dickson*, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton and Roland W. Bürli,
{"title":"一种高效、选择性、CNS渗透的mGluR7变构激动剂CVN636的发现","authors":"Louise Dickson*, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton and Roland W. Bürli, ","doi":"10.1021/acsmedchemlett.2c00529","DOIUrl":null,"url":null,"abstract":"<p >The low affinity metabotropic glutamate receptor mGluR<sub>7</sub> has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR<sub>7</sub> agonists. Of particular interest is the chromane <b>CVN636</b>, a potent (EC<sub>50</sub> 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR<sub>7</sub> compared to not only other mGluRs, but also a broad range of targets. <b>CVN636</b> demonstrated CNS penetrance and efficacy in an <i>in vivo</i> rodent model of alcohol use disorder. <b>CVN636</b> thus has potential to progress as a drug candidate in CNS disorders involving mGluR<sub>7</sub> and glutamatergic dysfunction.</p>","PeriodicalId":20,"journal":{"name":"ACS Medicinal Chemistry Letters","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2023-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":"{\"title\":\"Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist\",\"authors\":\"Louise Dickson*, Martin Teall, Elodie Chevalier, Toni Cheung, Gemma M. Liwicki, Stephen Mack, Anne Stephenson, Kathryn White, Richard Fosbeary, David C. Harrison, Nicola L. Brice, Kevin Doyle, Roberto Ciccocioppo, Chaobo Wu, Sarah Almond, Toshal R. Patel, Philip Mitchell, Matt Barnes, Andrew P. Ayscough, Lee A. Dawson, Mark Carlton and Roland W. Bürli, \",\"doi\":\"10.1021/acsmedchemlett.2c00529\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The low affinity metabotropic glutamate receptor mGluR<sub>7</sub> has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR<sub>7</sub> agonists. Of particular interest is the chromane <b>CVN636</b>, a potent (EC<sub>50</sub> 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR<sub>7</sub> compared to not only other mGluRs, but also a broad range of targets. <b>CVN636</b> demonstrated CNS penetrance and efficacy in an <i>in vivo</i> rodent model of alcohol use disorder. <b>CVN636</b> thus has potential to progress as a drug candidate in CNS disorders involving mGluR<sub>7</sub> and glutamatergic dysfunction.</p>\",\"PeriodicalId\":20,\"journal\":{\"name\":\"ACS Medicinal Chemistry Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2023-03-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"2\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00529\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00529","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of CVN636: A Highly Potent, Selective, and CNS Penetrant mGluR7 Allosteric Agonist
The low affinity metabotropic glutamate receptor mGluR7 has been implicated in numerous CNS disorders; however, a paucity of potent and selective activators has hampered full delineation of the functional role and therapeutic potential of this receptor. In this work, we present the identification, optimization, and characterization of highly potent, novel mGluR7 agonists. Of particular interest is the chromane CVN636, a potent (EC50 7 nM) allosteric agonist which demonstrates exquisite selectivity for mGluR7 compared to not only other mGluRs, but also a broad range of targets. CVN636 demonstrated CNS penetrance and efficacy in an in vivo rodent model of alcohol use disorder. CVN636 thus has potential to progress as a drug candidate in CNS disorders involving mGluR7 and glutamatergic dysfunction.
期刊介绍:
ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to:
Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics)
Biological characterization of new molecular entities in the context of drug discovery
Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc.
Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry
Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources
Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response
Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic
Mechanistic drug metabolism and regulation of metabolic enzyme gene expression
Chemistry patents relevant to the medicinal chemistry field.