Discovery of a novel series of pyridone amides as Na V 1.8 inhibitors

The Na 1.8 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...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2024-03, Vol.101, p.129655
Hauptverfasser: Wang, Yanfang, Hu, Shilong, Chen, Yuhao, Chen, Meiyuan, Zhang, Di, Liu, Wencheng, Chen, Chunxia, Gan, Yu, Luo, Menglan, Ke, Bowen
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Sprache:eng
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Zusammenfassung:The Na 1.8 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 1.8, we developed two series with a total of 19 molecules and examined their binding affinity to Na 1.8 in vitro and analgesic effect in vivo. One compound, named 2j, stood out with notable activity against the Na 1.8 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.
ISSN:1464-3405
DOI:10.1016/j.bmcl.2024.129655