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.
Source:
Journal reference:
Zeng, F, et al. (2021) 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. doi.org/10.1016/j.apsb.2020.10.008.
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