Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain

Xuetao Chen, Danyan Cao, Chihong Liu, Fanying Meng, Zijian Zhang, Rujun Xu, Yuanyuan Tong, Yabing Xin, Weikun Zhang, Wenjing Kang, Qichao Bao, Jingkang Shen, Bing Xiong, Qidong You, Zhengyu Jiang

Research output: Contribution to journalArticlepeer-review

Abstract

Neuropathic pain (NP) is an intolerable pain syndrome that arises from continuous inflammation and excitability after nerve injury. Only a few NP therapeutics are currently available, and all of them do not provide adequate pain relief. Herein, we report the discovery of a selective and potent inhibitor of the bromodomain and extra-terminal (BET) proteins for reducing neuroinflammation and excitability to treat NP. Starting with the screening hit 1 from an in-house compound library, iterative optimization resulted in the potent BET inhibitor DDO-8926 with a unique binding mode and a novel chemical structure. DDO-8926 exhibits excellent BET selectivity and favorable drug-like properties. In mice with spared nerve injury, DDO-8926 significantly alleviated mechanical hypersensitivity by inhibiting pro-inflammatory cytokine expression and reducing excitability. Collectively, these results implicate that DDO-8926 is a promising agent for the treatment of NP.

Original languageEnglish (US)
Pages (from-to)8725-8744
Number of pages20
JournalJournal of medicinal chemistry
Volume66
Issue number13
DOIs
StatePublished - Jul 13 2023
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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