New aryl and acylsulfonamides as state-dependent inhibitors of Nav1.3 voltage-gated sodium channel

Voltage-gated sodium channels (Na_vs) play an essential role in neurotransmission, and their dysfunction is often a cause of various neurological disorders. The Na_v1.3 isoform is found in the CNS and upregulated after injury in the periphery, but its role in human physiology has not yet been fully elucidated. Reports suggest that selective Na_v1.3 inhibitors could be used as novel therapeutics to treat pain or neurodevelopmental disorders. Few selective inhibitors of this channel are known in the literature. In this work, we report the discovery of a new series of aryl and acylsulfonamides as state-dependent inhibitors of Na_v1.3 channels. Using a ligand-based 3D similarity search and subsequent hit optimization, we identified and prepared a series of 47 novel compounds and tested them on Na_v1.3, Na_v1.5, and a selected subset also on Na_v1.7 channels in a QPatch patch-clamp electrophysiology assay. Eight compounds had an IC₅₀ value of less than 1 μM against the Na_v1.3 channel inactivated state, with one compound displaying an IC₅₀ value of 20 nM, whereas activity against the inactivated state of the Na_v1.5 channel and Na_v1.7 channel was approximately 20-fold weaker. None of the compounds showed use-dependent inhibition of the cardiac isoform Na_v1.5 at a concentration of 30 μM. Further selectivity testing of the most promising hits was measured using the two-electrode voltage-clamp method against the closed state of the Na_v1.1-Na_v1.8 channels, and compound 15b displayed small, yet selective, effects against the Na_v1.3 channel, with no activity against the other isoforms. Additional selectivity testing of promising hits against the inactivated state of the Na_v1.3, Na_v1.7, and Na_v1.8 channels revealed several compounds with robust and selective activity against the inactivated state of the Na_v1.3 channel among the three isoforms tested. Moreover, the compounds were not cytotoxic at a concentration of 50 μM, as demonstrated by the assay in human HepG2 cells (hepatocellular carcinoma cells). The novel state-dependent inhibitors of Na_v1.3 discovered in this work provide a valuable tool to better evaluate this channel as a potential drug target.

Acylsulfonamide; Arylsulfonamide; Inhibitor; Na(v) channel; Na(v)1.3; Voltage-gated sodium channel.