Discovery and Optimization of Novel hDHODH Inhibitors for the Treatment of Inflammatory Bowel Disease

• Published in: Journal of medicinal chemistry 2023-11, Vol.66 (21), p.14755-14786
• Main Authors: Zhou, Xia, Gou, Kun, Xu, Jing, Jian, Lunan, Luo, Yuan, Li, Chungen, Guan, Xinqi, Qiu, Jiahao, Zou, Jiao, Zhang, Yu, Zhong, Xi, Zeng, Ting, Zhou, Yue, Xiao, Yuzhou, Yang, Xinyu, Chen, Weijie, Gao, Ping, Liu, Chunqi, Zhou, Yang, Tao, Lei, Liu, Xingchen, Cen, Xiaobo, Chen, Qiang, Sun, Qingxiang, Luo, Youfu, Zhao, Yinglan
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01365

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase (hDHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1H-pyrazolo­[3,4-b]­pyridine scaffold was identified as an hDHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1H-pyrrolo­[2,3-b]­pyridin-3-yl)-5-cyclopropylpyrimidin-4-amine (w2), which was found to be the most promising and drug-like compound with potent inhibitory activity against hDHODH (IC50 = 173.4 nM). Compound w2 demonstrated acceptable pharmacokinetic characteristics and alleviated the severity of acute ulcerative colitis induced by dextran sulfate sodium in a dose-dependent manner. Notably, w2 exerted better therapeutic effects on ulcerative colitis than hDHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising hDHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.