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

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Discovery of 1H-Imidazo[4,5-b]pyridine Derivatives as Potent and Selective BET Inhibitors for the Management of Neuropathic Pain
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-06-29 , 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}

Affiliation

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.

中文翻译：

发现 1H-咪唑并[4,5-b]吡啶衍生物作为治疗神经性疼痛的有效和选择性 BET 抑制剂

神经性疼痛（NP）是一种难以忍受的疼痛综合征，由神经损伤后持续的炎症和兴奋性引起。目前只有少数 NP 疗法可用，并且所有这些疗法都不能提供足够的疼痛缓解。在此，我们报告发现了一种选择性有效的溴结构域和额外末端 (BET) 蛋白抑制剂，可减少神经炎症和治疗 NP 的兴奋性。从内部化合物库中的筛选命中1开始，迭代优化产生了具有独特结合模式和新颖化学结构的有效 BET 抑制剂DDO-8926 。DDO-8926表现出优异的 BET 选择性和良好的药物样特性。在神经未受损伤的小鼠中，DDO-8926通过抑制促炎细胞因子的表达和降低兴奋性，显着减轻机械超敏反应。总的来说，这些结果表明DDO-8926是一种有前途的 NP 治疗药物。

更新日期：2023-06-29

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