Discovery of Novel Orally Bioavailable STING Inhibitors with 4,5,6,7-Tetrahydropyrazolo[1,5- a ]pyrazine Moiety for STING-Mediated Inflammatory Disorders

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway plays a pivotal role in host defense against pathogenic microbes and tumors. However, aberrant activation of this pathway is tightly associated with a wide spectrum of inflammatory and autoimmune disorders, positioning STING inhibition as a promising therapeutic strategy. In this study, we designed and synthesized a series of novel 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine derivatives as STING inhibitors. Compound 37 displayed potent STING inhibitory activity and favorable in vivo pharmacokinetic properties and safety. Further studies revealed that 37 blocks STING palmitoylation, thereby suppressing downstream signaling pathway activation. Oral administration of 37 exhibited significant anti-inflammatory effects in 10-carboxymethyl-9-acridanone (CMA)-challenged mice, Trex1−/− mice and cisplatin-induced acute kidney injury (AKI) mice. Collectively, compound 37 represents a novel orally bioavailable STING inhibitor with therapeutic potential against STING-driven inflammatory and autoimmune diseases.