文献类型：期刊文献

英文题名：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：Zeng, Fanxun[1];Li, Shiliang[2];Yang, Guantian[1];Luo, Yating[2];Qi, Tiantian[2];Liang, Yingfan[2];Yang, Tingyuan[2];Zhang, Letian[1];Wang, Rui[2];Zhu, Lili[2];Li, Honglin[2];Xu, Xiaoyong[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab Chem Biol, Shanghai 200237, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China

年份：2021

卷号：11

期号：3

起止页码：795

外文期刊名：ACTA PHARMACEUTICA SINICA B

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000629336800015)】；

基金：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.

语种：英文

外文关键词：DHODH; De novo pyrimidine biosynthesis; DHODH inhibitors; Acrylamide derivatives; Rheumatoid arthritis

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 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. (C) 2021 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.