Accumulating evidence has demonstrated a critical pathological role of oxysterol receptor GPR183 in various inflammatory and autoimmune diseases, including inflammatory bowel disease (IBD). However, the currently reported GPR183 antagonists are very limited and not qualified for studies due to their inferior druglike properties. Herein, we conducted a structural elaboration focusing on improving its PK and safety profile based on a reference antagonist NIBR189. Of note, compound , bearing an aminobenzothiazole motif, exhibited reduced hERG inhibition, improved PK properties, and robust antagonistic activity (IC = 0.82 nM) with high selectivity against GPR183. Moreover, compound displayed strong antimigration and anti-inflammatory activity in monocytes. Oral administration of compound effectively improved the pathological symptoms of DSS-induced experimental colitis. All of these findings demonstrate that compound is a novel and promising GPR183 antagonist suitable for further investigation to treat IBD.
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