2. Academic Validation
  3. Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[ d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

Discovery of a Highly Potent Oxysterol Receptor GPR183 Antagonist Bearing the Benzo[ d]thiazole Structural Motif for the Treatment of Inflammatory Bowel Disease (IBD)

  • J Med Chem. 2024 Feb 28. doi: 10.1021/acs.jmedchem.3c01905.
Ruoqing Zeng 1 2,  Meimiao Fang 3,  Ancheng Shen 1 4 2,  Xiaolei Chai 3,  Yumiao Zhao 3,  Mingyao Liu 3,  Lingfeng Zhu 5,  Weiwei Rui 6,  Bo Feng 6,  Liang Hong 1 2,  Chunyong Ding 1 2,  Zilan Song 1 2,  Weiqiang Lu 3,  Ao Zhang 1 4 2 5
Affiliations

Affiliations

  • 1 Shanghai Frontiers Science Center for Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2 National Key Laboratory of Innovative Immunotherapy, Shanghai 200240, China.
  • 3 Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 4 Lingang Laboratory, Shanghai 200210, China.
  • 5 Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 6 Department of General Surgery and Department of Pathology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
PMID: 38417036 DOI: 10.1021/acs.jmedchem.3c01905
Abstract

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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