Design, synthesis, and biological evaluation of aryl urea derivatives as novel STING inhibitors based on SN-011

Abnormal activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon genes (STING) pathway drives excessive inflammatory responses and plays a key role in the pathological process of various inflammatory diseases, and thus STING inhibitors hold great promise as anti-inflammatory agents. In this work, we report a series of novel aryl urea derivatives as STING inhibitors. Among the 40 synthesized derivatives, compound W23 exhibited potent inhibitory activity against STING and effectively blocked STING downstream signaling transduction. Furthermore, topical administration of W23 ameliorated psoriatic skin lesions and attenuated cutaneous inflammation in imiquimod-induced psoriasis mouse model, with efficacy comparable to the commercial benvitimod cream. Collectively, compound W23 represents a potent STING inhibitor with the potential to reverse STING-mediated inflammatory responses and alleviate immune disorders. Our work provides some novel SN-011 derivatives as STING inhibitors for future research.