Discovery of a
Highly Potent Oxysterol Receptor GPR183
Antagonist Bearing the Benzo[d]thiazole Structural
Motif for the Treatment of Inflammatory Bowel Disease (IBD)
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 in vivo 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 33, bearing an aminobenzothiazole
motif, exhibited reduced hERG inhibition, improved PK properties,
and robust antagonistic activity (IC50 = 0.82 nM) with
high selectivity against GPR183. Moreover, compound 33 displayed strong in vitro antimigration and anti-inflammatory
activity in monocytes. Oral administration of compound 33 effectively improved the pathological symptoms of DSS-induced experimental
colitis. All of these findings demonstrate that compound 33 is a novel and promising GPR183 antagonist suitable for further
investigation to treat IBD.