Discovery of a novel series of pyridone amides as Na1.8 inhibitors.

The Na1.8 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 Na1.8, we developed two series with a total of 19 molecules and examined their binding affinity to Na1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the Na1.8 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.