Discovery of Arylsulfonamide Na_v1.7 Inhibitors: IVIVC, MPO Methods, and Optimization of Selectivity Profile

The voltage-gated sodium channel Na_v1.7 continues to be a high-profile target for the treatment of various pain afflictions due to its strong human genetic validation. While isoform selective molecules have been discovered and advanced into the clinic, to date, this target has yet to bear fruit in the form of marketed therapeutics for the treatment of pain. Lead optimization efforts over the past decade have focused on selectivity over Na_v1.5 due to its link to cardiac side effects as well as the translation of preclinical efficacy to man. Inhibition of Na_v1.6 was recently reported to yield potential respiratory side effects preclinically, and this finding necessitated a modified target selectivity profile. Herein, we report the continued optimization of a novel series of arylsulfonamide Na_v1.7 inhibitors to afford improved selectivity over Na_v1.6 while maintaining rodent oral bioavailability through the use of a novel multiparameter optimization (MPO) paradigm. We also report in vitro–in vivo correlations from Na_v1.7 electrophysiology protocols to preclinical models of efficacy to assist in projecting clinical doses. These efforts produced inhibitors such as compound 19 with potency against Na_v1.7, selectivity over Na_v1.5 and Na_v1.6, and efficacy in behavioral models of pain in rodents as well as inhibition of rhesus olfactory response indicative of target modulation.