Human dihydroorotate dehydrogenase(DHODH) is a viable target for the development of therapeutics to treat cancer andimmunological diseases, such asrheumatoid arthritis(RA), psoriasis andmultiple sclerosis(MS).
The authors designed and synthesized a series of acrylamide-based novel DHODH inhibitors as potential RA treatment agents. 2-Acrylamidobenzoic acid analog11was identified as the lead compound for structure-activity relationship (SAR) studies.
The replacement of thephenyl group with naphthylmoieties 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 IC50values of 41, 44, 32, and 42nmol/L, respectively.
The most potent compound 54 also displayed favorable pharmacokinetic(PK) profiles and encouraging invivoanti-arthritic effects in a dose-dependent manner.
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.