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

Herein, we report the discovery and optimization of a series of orally bioavailable acyl sulfonamide Na _V 1.7 inhibitors that are selective for Na _V 1.7 over Na _V 1.5 and highly efficacious in in vivo models of pain and hNa _V 1.7 target engagement. An analysis of the physicochemical properties of literature Na _V 1.7 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 _V 1.7 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 _V 1.7 and improvement of human metabolic stability, utilizing induced fit docking in our previously disclosed X-ray cocrystal of the Na _V 1.7 voltage sensing domain. These investigations culminated in the discovery of tool compound 33, one of the most potent and efficacious Na _V 1.7 inhibitors reported to date.