Identification of Selective Acyl Sulfonamide-Cycloalkylether Inhibitors of the Voltage-Gated Sodium Channel (NaV) 1.7 with Potent Analgesic Activity

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na_V1.7 inhibitors that are selective for Na_V1.7 over Na_V1.5 and highly efficacious in in vivo models of pain and hNa_V1.7 target engagement. An analysis of the physicochemical properties of literature Na_V1.7 inhibitors suggested that acyl sulfonamides with high f_sp3 could overcome some of the pharmacokinetic (PK) and efficacy challenges seen with existing series. Parallel library syntheses lead to the identification of analogue 7, which exhibited moderate potency against Na_V1.7 and an acceptable PK profile in rodents, but relatively poor stability in human liver microsomes. Further, design strategy then focused on the optimization of potency against hNa_V1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the Na_V1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious Na_V1.7 inhibitors reported to date.