Discovery of orally available benzimidazole-based STING antagonists with in vivo activity.

Stimulator of interferon genes (STING) plays a pivotal role in the innate immune system. However, aberrant activation of the STING pathway has been implicated in the development of autoimmune and inflammatory diseases. Herein, we report the discovery of a series of novel, orally available benzimidazole derivatives as STING antagonists. S-570 (21b) was identified as a potent STING antagonist that covalently binds to Cys91. Oral administration of S-570 in a CMA-induced inflammation mouse model significantly suppressed the production of IFN-β, IL-6, and TNF-α.