Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 with Efficacy in Rodent Pain Models

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• 作者：Thilo Focken ; Shifeng Liu ; Navjot Chahal ; Maxim Dauphinais ; Michael E. Grimwood ; Sultan Chowdhury ; Ivan Hemeon ; Paul Bichler ; David Bogucki ; Matthew Waldbrook ; Girish Bankar ; Luis E. Sojo ; Clint Young ; Sophia Lin ; Noah Shuart ; Rainbow Kwan ; Jodie Pang ; Jae H. Chang ; Brian S. Safina ; Daniel P. Sutherlin ; J. P. Johnson Jr. ; Christoph M. Dehnhardt ; Tarek S. Mansour ; Renata M. Oballa ; Charles J. Cohen ; C. Lee Robinette
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：277-282
• 全文大小：349K
• ISSN：1948-5875

文摘

We report on a novel series of aryl sulfonamides that act as nanomolar potent, isoform-selective inhibitors of the human sodium channel hNa_V1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNa_V1.7 while minimizing off-target safety concerns and generated compound 3. This agent displayed significant analgesic effects in rodent models of acute and inflammatory pain and demonstrated that binding to the voltage sensor domain 4 site of Na_V1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNa_V1.7 as a drug target for the treatment of pain.