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

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

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 IC(50) 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.