Discovery of a novel series of pyridone amides as Na < sub > V < /sub > 1.8 inhibitors

Bioorg Med Chem Lett. 2024 Feb 11:129655. doi: 10.1016/j.bmcl.2024.129655. Online ahead of print.ABSTRACTThe NaV1.8 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 NaV1.8, we developed two series with a total of 19 molecules and examined their binding affinity to NaV1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the NaV1.8 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.PMID:38350529 | DOI:10.1016/j.bmcl.2024.129655

Source: Bioorganic and Medicinal Chemistry Letters - February 13, 2024 Category: Chemistry Authors: Yanfang Wang Shilong Hu Yuhao Chen Meiyuan Chen Di Zhang Wencheng Liu Chunxia Chen Yu Gan Menglan Luo Bowen Ke Source Type: research