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

被引：1

作者：

Wang, Yanfang ^{[1
]}

Hu, Shilong ^{[1
]}

Chen, Yuhao ^{[1
]}

Chen, Meiyuan ^{[1
]}

Zhang, Di ^{[1
]}

Liu, Wencheng ^{[1
]}

Chen, Chunxia ^{[1
]}

Gan, Yu ^{[1
]}

Luo, Menglan ^{[1
]}

Ke, Bowen ^{[1
]}

机构：

[1] Sichuan Univ, West China Hosp, Natl Local Joint Engn Res Ctr Translat Med Anesthe, Lab Anesthesia & Crit Care Med,Dept Anesthesiol, Chengdu 610041, Sichuan, Peoples R China

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2024年 / 101卷

基金：

中国国家自然科学基金;

关键词：

Pyridone amides; Chronic pain; Sodium channel blocker; NaV1.8; NA(V)1.8 SODIUM-CHANNEL; EFFICACY; POTENT; PAIN; BLOCKERS; MODELS;

D O I：

10.1016/j.bmcl.2024.129655

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 VX150 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.

引用

页数：9

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