Original articles
Fanxun Zeng, Shiliang Li, Guantian Yang, Yating Luo, Tiantian Qi, Yingfan Liang, Tingyuan Yang, Letian Zhang, Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu. Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 795-809

Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis
Fanxun Zenga, Shiliang Lib, Guantian Yanga, Yating Luob, Tiantian Qib, Yingfan Liangb, Tingyuan Yangb, Letian Zhanga, Rui Wangb, Lili Zhub, Honglin Lib, Xiaoyong Xua
a Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China;
b Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science & Technology, Shanghai 200237, China
Human dihydroorotate dehydrogenase (DHODH) is a viable target for the development of therapeutics to treat cancer and immunological diseases, such as rheumatoid arthritis (RA), psoriasis and multiple sclerosis (MS). Herein, a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents were designed and synthesized. 2-Acrylamidobenzoic acid analog 11 was identified as the lead compound for structure—activity relationship (SAR) studies. The replacement of the phenyl group with naphthyl moieties improved inhibitory activity significantly to double-digit nanomolar range. Further structure optimization revealed that an acrylamide with small hydrophobic groups (Me, Cl or Br) at the 2-position was preferred. Moreover, adding a fluoro atom at the 5-position of the benzoic acid enhanced the potency. The optimization efforts led to potent compounds 42 and 53-55 with IC50 values of 41, 44, 32, and 42 nmol/L, respectively. The most potent compound 54 also displayed favorable pharmacokinetic (PK) profiles and encouraging in vivo anti-arthritic effects in a dose-dependent manner.
Key words:    DHODH    De novo pyrimidine biosynthesis    DHODH inhibitors    Acrylamide derivatives    Rheumatoid arthritis   
Received: 2020-07-01     Revised: 2020-09-17
DOI: 10.1016/j.apsb.2020.10.008
Funds: This work was supported by the National Key Research and Development Program (2017YFD0200505 to Xiaoyong Xu, 2016YFA0502304 to Honglin Li, China); the National Natural Science Foundation of China (81825020 to Honglin Li, 81803437 to Shiliang Li); the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (2018ZX09711002, China); the Fundamental Research Funds for the Central Universities; and the Shanghai Foundation of Science and Technology (15431902100 to Xiaoyong Xu). Shiliang Li is also sponsored by Shanghai Sailing Program (No. 18YF1405100, China). Honglin Li is also sponsored by the National Program for Special Supports of Eminent Professionals and National Program for Support of Top-Notch Young Professionals, China. We thank Dr. Wei Wang for English proofreading of this manuscript.
Corresponding author: Rui Wang, Lili Zhu, Honglin Li, Xiaoyong Xu     Email:ruiwang@ecust.edu.cn;zhulfl@ecust.edu.cn;hlli@ecust.edu.cn;xyxu@ecust.edu.cn
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Fanxun Zeng
Shiliang Li
Guantian Yang
Yating Luo
Tiantian Qi
Yingfan Liang
Tingyuan Yang
Letian Zhang
Rui Wang
Lili Zhu
Honglin Li
Xiaoyong Xu

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