Discovery and Optimization of Novel h DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease.

As a key rate-limiting enzyme in the de novo synthesis of pyrimidine nucleotides, human dihydroorotate dehydrogenase ( h DHODH) is considered a known target for the treatment of autoimmune diseases, including inflammatory bowel disease (IBD). Herein, BAY 41-2272 with a 1 H -pyrazolo[3,4- b ]pyridine scaffold was identified as an h DHODH inhibitor by screening an active compound library containing 5091 molecules. Further optimization led to 2-(1-(2-chloro-6-fluorobenzyl)-1 H -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 h DHODH (IC 50 = 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 h DHODH inhibitor vidofludimus and Janus kinase (JAK) inhibitor tofacitinib. Taken together, w2 is a promising h DHODH inhibitor for the treatment of IBD and deserves to be developed as a preclinical candidate.