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.

中文翻译：

---

发现一种具有苯并[d]噻唑结构基序的高效氧甾醇受体 GPR183 拮抗剂，用于治疗炎症性肠病 (IBD)

越来越多的证据表明氧甾醇受体 GPR183 在各种炎症和自身免疫性疾病（包括炎症性肠病 (IBD)）中发挥着关键的病理作用。然而，目前报道的GPR183拮抗剂非常有限，并且由于其类药特性较差，不适合体内研究。在此，我们基于参考拮抗剂 NIBR189 进行了结构阐述，重点是改善其 PK 和安全性。值得注意的是，带有氨基苯并噻唑基序的化合物33表现出减少的 hERG 抑制、改善的 PK 特性和强大的拮抗活性 (IC ₅₀ = 0.82 nM)，并对 GPR183 具有高选择性。此外，化合物33在体外对单核细胞表现出很强的抗迁移和抗炎活性。口服化合物33可有效改善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33是一种新型且有前途的GPR183拮抗剂，适合进一步研究治疗IBD。