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

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

  • J Med Chem. 2023 Jul 13;66(13):8725-8744. doi: 10.1021/acs.jmedchem.3c00372.
Xuetao Chen 1 2,  Danyan Cao 3,  Chihong Liu 1 2,  Fanying Meng 1 2,  Zijian Zhang 1 2,  Rujun Xu 1 2,  Yuanyuan Tong 1 2,  Yabing Xin 1 2,  Weikun Zhang 1 2,  Wenjing Kang 1 2,  Qichao Bao 1,  Jingkang Shen 3,  Bing Xiong 3 4,  Qidong You 1 2,  Zhengyu Jiang 1 2
Affiliations

Affiliations

  • 1 Jiang Su Key Laboratory of Drug Design and Optimization and State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
PMID: 37382379 DOI: 10.1021/acs.jmedchem.3c00372
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.

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