Shaoyi Sun , Sultan Chowdhury , Ivan Hemeon , Abid Hasan , Michael S. Wilson , Phillipe Bergeron , Qi Jia , Alla Y. Zenova , Mike E. Grimwood , Wei Gong , Shannon M. Decker , Paul Bichler , Jean-Christophe Andrez , Thilo Focken , Theresa Ngyuen , Jiuxiang Zhu , Andrew D. White , Girish Bankar , Sarah Howard , Elaine Chang , Christoph M. Dehnhardt
{"title":"发现新型环戊烷羧酸作为 NaV1.7 的强效选择性抑制剂。","authors":"Shaoyi Sun , Sultan Chowdhury , Ivan Hemeon , Abid Hasan , Michael S. Wilson , Phillipe Bergeron , Qi Jia , Alla Y. Zenova , Mike E. Grimwood , Wei Gong , Shannon M. Decker , Paul Bichler , Jean-Christophe Andrez , Thilo Focken , Theresa Ngyuen , Jiuxiang Zhu , Andrew D. White , Girish Bankar , Sarah Howard , Elaine Chang , Christoph M. Dehnhardt","doi":"10.1016/j.bmcl.2024.130033","DOIUrl":null,"url":null,"abstract":"<div><div>Discovery efforts leading to the identification of cyclopentane carboxylic acid <strong>31</strong>, a potent inhibitor of Na<sub>V</sub>1.7 that showed high selectivity over Na<sub>V</sub>1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of <strong>31</strong> include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na<sub>V</sub>1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.</div></div>","PeriodicalId":256,"journal":{"name":"Bioorganic & Medicinal Chemistry Letters","volume":"116 ","pages":"Article 130033"},"PeriodicalIF":2.5000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7\",\"authors\":\"Shaoyi Sun , Sultan Chowdhury , Ivan Hemeon , Abid Hasan , Michael S. Wilson , Phillipe Bergeron , Qi Jia , Alla Y. Zenova , Mike E. Grimwood , Wei Gong , Shannon M. Decker , Paul Bichler , Jean-Christophe Andrez , Thilo Focken , Theresa Ngyuen , Jiuxiang Zhu , Andrew D. White , Girish Bankar , Sarah Howard , Elaine Chang , Christoph M. Dehnhardt\",\"doi\":\"10.1016/j.bmcl.2024.130033\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Discovery efforts leading to the identification of cyclopentane carboxylic acid <strong>31</strong>, a potent inhibitor of Na<sub>V</sub>1.7 that showed high selectivity over Na<sub>V</sub>1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of <strong>31</strong> include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted Na<sub>V</sub>1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.</div></div>\",\"PeriodicalId\":256,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry Letters\",\"volume\":\"116 \",\"pages\":\"Article 130033\"},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-11-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry Letters\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0960894X24004359\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry Letters","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0960894X24004359","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Discovery of novel cyclopentane carboxylic acids as potent and selective inhibitors of NaV1.7
Discovery efforts leading to the identification of cyclopentane carboxylic acid 31, a potent inhibitor of NaV1.7 that showed high selectivity over NaV1.5 and exhibited robust analgesic effects in an inherited erythromelalgia (IEM) transgenic mouse assay, are described herein. Key design elements that culminated in the discovery of 31 include exploration of proline substituents, replacement of the proline warhead with cyclopentane carboxylic acid, that led to significantly boosted NaV1.7 potency, and replacement of the metabolically labile adamantane motif with the 2,6-dichlorobenzyl substituted piperidine system, that addressed metabolic instability and led to a significant improvement in PK.
期刊介绍：
Bioorganic & Medicinal Chemistry Letters presents preliminary experimental or theoretical research results of outstanding significance and timeliness on all aspects of science at the interface of chemistry and biology and on major advances in drug design and development. The journal publishes articles in the form of communications reporting experimental or theoretical results of special interest, and strives to provide maximum dissemination to a large, international audience.
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