2. Academic Validation
  3. Discovery and Optimization of Novel h DHODH Inhibitors for the Treatment of Inflammatory Bowel Disease

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

  • J Med Chem. 2023 Oct 23. doi: 10.1021/acs.jmedchem.3c01365.
Xia Zhou 1 2,  Kun Gou 1,  Jing Xu 1,  Lunan Jian 1,  Yuan Luo 1,  Chungen Li 1,  Xinqi Guan 1,  Jiahao Qiu 1,  Jiao Zou 1,  Yu Zhang 3,  Xi Zhong 4,  Ting Zeng 4,  Yue Zhou 1,  Yuzhou Xiao 1,  Xinyu Yang 4,  Weijie Chen 4,  Ping Gao 1,  Chunqi Liu 1,  Yang Zhou 1,  Lei Tao 1,  Xingchen Liu 4,  Xiaobo Cen 5,  Qiang Chen 1,  Qingxiang Sun 1 6,  Youfu Luo 1,  Yinglan Zhao 1 4
Affiliations

Affiliations

  • 1 Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Green Pharmaceutical Technology Key Laboratory of Luzhou, Central Nervous System Drug Key Laboratory of Sichuan Province, Department of Medicinal Chemistry, School of Pharmacy, Southwest Medical University, Luzhou 646000, China.
  • 3 School of Medicine, Tibet University, Lhasa 850000, China.
  • 4 West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 5 National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6 Department of Pulmonary and Critical Care Medicine, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
PMID: 37870434 DOI: 10.1021/acs.jmedchem.3c01365
Abstract

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.

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