化学
噻唑
炎症性肠病
敌手
药理学
体内
氧甾醇
立体化学
受体
疾病
内科学
生物化学
医学
胆固醇
生物技术
生物
作者
Ruoqing Zeng,Meimiao Fang,Ancheng Shen,Xiaolei Chai,Yalei Zhao,Mingyao Liu,Lingfeng Zhu,Weiwei Rui,Bo Feng,Liang Hong,Chunyong Ding,Zilan Song,Weiqiang Lü,Ao Zhang
标识
DOI:10.1021/acs.jmedchem.3c01905
摘要
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.
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