2. Academic Validation
  3. Discovery of a novel series of pyridone amides as NaV1.8 inhibitors

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

  • Bioorg Med Chem Lett. 2024 Feb 11:101:129655. doi: 10.1016/j.bmcl.2024.129655.
Yanfang Wang 1,  Shilong Hu 1,  Yuhao Chen 1,  Meiyuan Chen 1,  Di Zhang 1,  Wencheng Liu 1,  Chunxia Chen 1,  Yu Gan 1,  Menglan Luo 1,  Bowen Ke 2
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
  • 2 Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China. Electronic address: bowenke@scu.edu.cn.
PMID: 38350529 DOI: 10.1016/j.bmcl.2024.129655
Abstract

The 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.

Keywords

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

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