Synthesis and Pharmacological Evaluation of Tetrahydro-γ-carboline Derivatives as Potent Anti-inflammatory Agents Targeting Cyclic GMP–AMP Synthase

作者：Jing Tan, Bing Wu, Tingting Chen, Fan Chen, Jiannan Zhao, Chaodong Xiong, Chunlan Feng, Ruoxuan Xiao, Chunyong Ding, Wei Tang, Ao Zhang · 发表于：Journal of Medicinal Chemistry · 年份：2021 · DOI：10.1021/acs.jmedchem.1c00398 · 被引用次数：57 · 研究领域：interferon and immune responses、RNA and protein synthesis mechanisms、Cytokine Signaling Pathways and Interactions

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 IC 50 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.