Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.
J Med Chem
; 67(8): 6268-6291, 2024 Apr 25.
Article
in En
| MEDLINE
| ID: mdl-38619191
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrrolidines
/
Carbazoles
/
Drug Design
/
Acute Lung Injury
/
Nucleotidyltransferases
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2024
Document type:
Article
Affiliation country:
Country of publication: