Discovery of new indole-based acylsulfonamide Nav1.7 inhibitors

Abstract Screening of 100 acylsulfonamides from the Bristol-MyersSquibb compound collection identified the C3-cyclohexyl indole 6 as a potent Na v 1.7 inhibitor. Replacement of the C2 furanyl ring of 6 with a heteroaryl moiety or truncation of this group led to the identification of 4 analogs with hNa v 1.7 IC 50 values under 50 nM. Fluorine substitution of the truncated compound 12 led to 34 with improved potency and isoform selectivity. The inverted indole 36 also maintained good activity. Both 34 and 36 exhibited favorable CYP inhibition profiles, good membrane permeability and a low efflux ratio and, therefore, represent new leads in the search for potent and selective Na v 1.7 inhibitors to treat pain.