2. Academic Validation
  3. 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

  • J Med Chem. 2021 Jun 10;64(11):7667-7690. doi: 10.1021/acs.jmedchem.1c00398.
Jing Tan 1 2 3,  Bing Wu 1 3,  Tingting Chen 2,  Chen Fan 1 3,  Jiannan Zhao 1 2 3 4,  Chaodong Xiong 1 2 3,  Chunlan Feng 1 3,  Ruoxuan Xiao 2,  Chunyong Ding 2 5,  Wei Tang 1 3,  Ao Zhang 1 2 3 4 5
Affiliations

Affiliations

  • 1 Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 Pharm-X Center, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 5 Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200240, China.
PMID: 34044539 DOI: 10.1021/acs.jmedchem.1c00398
Abstract

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.

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