The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na(v)1.7

摘要

The voltage gated sodium channel Na(v)1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Na(v)1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Na(v)1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Na(v)1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Na(v)1.7 inhibitor with a thousand-fold selectivity over Na(v)1.5 and negligible CYP inhibition. (C) 2014 Elsevier Ltd. All rights reserved.