Design, synthesis, molecular modeling, and biological evaluation of acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase for the treatment of rheumatoid arthritis  

作　　者：Fanxun Zeng Shiliang Li Guantian Yang Yating Luo Tiantian Qi Yingfan Liang Tingyuan Yang Letian Zhang Rui Wang Lili Zhu Honglin Li Xiaoyong Xu 

机构地区：[1]Shanghai Key Laboratory of Chemical Biology,School of Pharmacy,East China University of Science&Technology,Shanghai 200237,China [2]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

出　　处：《Acta Pharmaceutica Sinica B》2021年第3期795-809,共15页药学学报（英文版）

基　　金：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, 81803437to 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;the Shanghai Foundation of Science and Technology (15431902100 to Xiaoyong Xu);sponsored by Shanghai Sailing Program (No. 18YF1405100,China);sponsored by the National Program for Special Supports of Eminent Professionals;National Program for Support of Top-Notch Young Professionals,China。

摘　　要：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 structureeactivity 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.

关 键 词：DHODH De novo pyrimidine biosynthesis DHODH inhibitors Acrylamide derivatives Rheumatoid arthritis 

分 类 号：R914[医药卫生—药物化学]