Acrylamide-based DHODH inhibitors are potential agents for treating rheumatoid arthritis
Reviewed by Emily Henderson, B.Sc.Apr 8 2021
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.