Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase.
Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP-AMP Synthase.
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DOI：
10.1021/acs.jmedchem.1c00398
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发表时间：
2021-05
影响因子：
7.3
通讯作者：
Jing Tan;B. Wu;Tingting Chen;Chen Fan;Jiannan Zhao;Chaodong Xiong;Chun-lan Feng;Ruoxuan Xiao;C. Ding;Wei Tang;Ao Zhang
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文献类型：
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作者：
Jing Tan;B. Wu;Tingting Chen;Chen Fan;Jiannan Zhao;Chaodong Xiong;Chun-lan Feng;Ruoxuan Xiao;C. Ding;Wei Tang;Ao Zhang
双链DNA激活环GMP-AMP合成酶（cGAS）与许多高炎症和自身免疫性疾病的发病机制有关，靶向cGAS的小分子已成为治疗这些疾病的一种新的治疗策略。然而，目前报道的cGAS抑制剂远远超过成熟，几乎没有显示出体内疗效。受化合物5 （G140）结构新颖性的启发，我们对其侧链和中心三环核心进行了结构优化，得到了几个亚系列的化合物，包括那些意外环化的复合物。含有n -甘酰基侧链的化合物25对h-和m-cGAS的IC50值分别为1.38和11.4 μM，是最有效的化合物。机理研究证实其直接靶向cGAS。此外，化合物25在脂多糖诱导的小鼠模型中显示出优越的体内抗炎作用。化合物25的令人鼓舞的结果为进一步追求cgas靶向抑制剂作为一种新的抗炎治疗方法提供了坚实的证据。
The activation of cyclic GMP-AMP synthase (cGAS) by double-stranded DNA is implicated in the pathogenesis of many hyperinflammatory and autoimmune diseases, and the cGAS-targeting small molecule has emerged as a novel therapeutic strategy for treating these diseases. However, the currently reported cGAS inhibitors are far beyond maturity, barely demonstrating in vivo efficacy. Inspired by the structural novelty of compound 5 (G140), we conducted a structural optimization on both its side chain and the central tricyclic core, leading to several subseries of compounds, including those unexpectedly cyclized complex ones. Compound 25 bearing an N-glycylglycinoyl side chain was identified as the most potent one with cellular IC50 values of 1.38 and 11.4 μM for h- and m-cGAS, respectively. Mechanistic studies confirmed its direct targeting of cGAS. Further, compound 25 showed superior in vivo anti-inflammatory effects in the lipopolysaccharide-induced mouse model. The encouraging result of compound 25 provides solid evidence for further pursuit of cGAS-targeting inhibitors as a new anti-inflammatory treatment.