Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury

  • J Med Chem. 2024 Apr 25;67(8):6268-6291. doi: 10.1021/acs.jmedchem.3c02229.
Mingjie Chen  1  2 ,  Shuyue Lei  3  4 ,  Zihua Zhou  1  2 ,  Meng Wang  5 ,  Chunlan Feng  3  4 ,  Xiaoling Gao  1  2 ,  Chunyong Ding  1  2 ,  Zilan Song  1  2 ,  Wei Tang  3  4 ,  Ao Zhang  1  2
Affiliations
  • 1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.
  • 3. State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. School of Medicine, Anhui University of Science and Technology, Huainan 232001, China.
PMID: 38619191 DOI: 10.1021/acs.jmedchem.3c02229
Abstract

Overactivation of Cyclic GMP-AMP Synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.

Products