Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

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• 作者：Isaac E. Marx ; Thomas A. Dineen ; Jessica Able ; Christiane Bode ; Howard Bregman ; Margaret Chu-Moyer ; Erin F. DiMauro ; Bingfan Du ; Robert S. Foti ; Robert T. Fremeau Jr. ; Hua Gao ; Hakan Gunaydin ; Brian E. Hall ; Liyue Huang ; Thomas Kornecook ; Charles R. Kreiman ; Daniel S. La ; Joseph Ligutti ; Min-Hwa Jasmine Lin ; Dong Liu ; Jeff S. McDermott ; Bryan D. Moyer ; Emily A. Peterson ; Jonathan T. Roberts ; Paul Rose ; Jean Wang ; Beth D. Youngblood ; Violeta Yu ; Matthew M. Weiss
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：7
• 期：12
• 页码：1062-1067
• 全文大小：314K
• ISSN：1948-5875

文摘

Human genetic evidence has identified the voltage-gated sodium channel Na_V1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of Na_V1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining Na_V1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.