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).
The authors designed and synthesized a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents. 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.
Featured image: Dihydroorotate dehydrogenase (DHODH) is an attracting target for the treatment of immunological diseases. A series of acrylamide-based novel DHODH inhibitors as potential rheumatoid arthritis (RA) treatment agents were designed and synthesized, among which 54 is the most potent one with good pharmacokinetic profiles and favorable in vivo anti-arthritic effects. © Acta Pharmaceutica Sinica B
Article reference: 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, Acta Pharmaceutica Sinica B, 2021, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2020.10.008 https://www.sciencedirect.com/science/article/pii/S2211383520307590?via%3Dihub
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