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
  • 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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