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
  • 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.