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.

中文翻译：

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螺[咔唑-3,3'-吡咯烷]衍生物作为cGAS抑制剂治疗急性肺损伤的设计、合成和药理学评价


环 GMP-AMP 合酶 (cGAS) 的过度激活与许多炎症和自身免疫性疾病的发生有关，并且用特定抑制剂抑制 cGAS 已被提议作为一种潜在的治疗策略。然而，仅有少数低效cGAS抑制剂被报道，并且很少适合临床研究。作为我们对已报道的cGAS抑制剂6 （G140）结构优化的延续，我们开发了一系列具有独特2-氮杂螺[4.5]癸烷结构基序的螺[咔唑-3,3'-吡咯烷]衍生物，其中化合物30d- S被认为对 cGAS 具有高细胞效应。该化合物在大鼠中表现出改善的血浆暴露、较低的清除率和 35% 的口服生物利用度。此外，在LPS诱导的急性肺损伤（ALI）小鼠模型中，口服30mg/kg化合物30d- S可显着减轻肺部炎症并减轻组织病理学变化。这些结果证实30d- S是一种新型有效的cGAS抑制剂，值得进一步研究。