Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
National Key Laboratory of Innovative Immunotherapy, Shanghai 200240, China.
J Med Chem. 2024 Mar 14;67(5):3520-3541. doi: 10.1021/acs.jmedchem.3c01905. Epub 2024 Feb 28.
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.
越来越多的证据表明，氧化固醇受体 GPR183 在各种炎症和自身免疫性疾病中具有关键的病理作用，包括炎症性肠病 (IBD)。然而，目前报道的 GPR183 拮抗剂非常有限，由于其较差的类药性，不适合进行研究。在此，我们根据参考拮抗剂 NIBR189 进行了结构修饰，重点改善其 PK 和安全性特征。值得注意的是，具有氨基苯并噻唑结构的化合物 表现出降低的 hERG 抑制作用、改善的 PK 特性和对 GPR183 的强拮抗活性（IC = 0.82 nM），具有高选择性。此外，化合物 在单核细胞中表现出强大的抗迁移和抗炎活性。化合物 的口服给药有效改善了 DSS 诱导的实验性结肠炎的病理症状。所有这些发现表明，化合物 是一种新型且有前途的 GPR183 拮抗剂，适合进一步研究用于治疗 IBD。
