Development of New Benzenesulfonamides As Potent and Selective Na_v1.7 Inhibitors for the Treatment of Pain

Abstract

By taking advantage of certain features in piperidine 4, we developed a novel series of cyclohexylamine- and piperidine-based benzenesulfonamides as potent and selective Na1.7 inhibitors. However, compound 24, one of the early analogs, failed to reduce phase 2 flinching in the mouse formalin test even at a dose of 100 mpk PO due to insufficient dorsal root ganglion (DRG) exposure attributed to poor membrane permeability. Two analogs with improved membrane permeability showed much increased DRG concentrations at doses of 30 mpk PO, but, confoundingly, only one of these was effective in the formalin test. More data are needed to understand the disconnect between efficacy and exposure relationships.

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation

“…Recent efforts to find new analgesics targeting sodium channels have focused on compounds that have high selectivity for Nav1.7 or Nav1.8 channels (e.g. Zhang et al, 2010; Kornecook et al, 2017; Wu et al, 2017; reviewed by Yekkirala et al, 2017) which are expressed in nociceptors but have little or no expression in heart or brain. Selectivity among sodium channel subtypes, or for sodium channels over other channel types, may be important for neutral compounds that are present systemically.…”

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

“…Several studies of arylsulfonamides have attributed accumulation of compound in the nerve as a key determinant of compound efficacy (Kornecook et al, 2017;Wu et al, 2017). We are unable to quantify the free concentration of compounds in mouse DRGs.…”

“…In both mice and humans, heterozygous loss of function does not eliminate pain response, suggesting that >50% block of Na V 1.7 is needed for robust analgesic activity. Highly selective antagonists of Na V 1.7 have been characterized in animal models (Alexandrou et al, 2016;DiMauro et al, 2016;Focken et al, 2016Focken et al, , 2018Marx et al, 2016;Storer et al, 2017;Teng et al, 2017;Weiss et al, 2017;Wu et al, 2017). Although these compounds demonstrate the feasibility of selectively targeting Na V 1.7, the in vivo studies raise serious concerns about the level of receptor occupancy required for efficacy.…”

Psychotropic Drugs for the Management of Chronic Pain and Itch

“…Therefore, at present, the efforts of many researchers are aimed at finding and improving such drugs and studying the analgesic action of already known blockers. Thus, the study [54] describes animal testing of new potential Nav1.7 blockers belonging to the class of benzenesulfonamides that have a better ability to penetrate the membrane than their predecessors. In the paper [55], a sulfonamide compound AMG8379 was described which, according to electrophysiological measurements, inhibited Nav1.7 in nanomolar concentrations, and showed an analgesic efficacy in experiments on rodents.…”