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

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.