Discovery of a novel series of pyridone amides as NaV1.8 inhibitors

Abstract

The Na_V1.8 channel, mainly found in the peripheral nervous system, is recognized as one of the key factors in chronic pain. The molecule VX-150 was initially promising in targeting this channel, but the phase II trials of VX-150 did not show expected pain relief results. By analyzing the interaction mode of VX-150 and Na_V1.8, we developed two series with a total of 19 molecules and examined their binding affinity to Na_V1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the Na_V1.8 channel and showed effective pain relief in models of chronic inflammatory pain and neuropathic pain. Our research points to 2j as a strong contender for developing safer pain-relief treatments.

Keywords: Chronic pain; Na(V)1.8; Pyridone amides; Sodium channel blocker.