A study conducted for the treatment of Rheumatoid Anrthritis shows Acrylamide derivatives as potent inhibitors of human dihydroorotate dehydrogenase (DHODH)

May, 2021 - By SMI

The study showcased potential agents which could act as an inhibitor of human dihydroorotate dehydrogenase (DHODH), a compound which serves as a viable target for developing different therapeutics that treat diseases including Rheumatoid Arthritis (RA)

Rheumatoid arthritis is a type of arthritis where the body’s immune system attacks its own tissues and joints leading to joint pains and other damages throughout the body. People suffering from rheumatoid arthritis complain of painful swelling in the joints of their hands and feet. As of now, there is no cure for rheumatoid arthritis (RA), while several studies are being conducted on the same.

According to the recent findings, an Acrylamide derivative could serve as a potential agent for treating RA by serving as a potential inhibitor of human dihydroorotate dehydrogenase (DHODH). The compound DHODH is considered as a viable target in the development of therapeutics treating cancer, immunological diseases like RA, psoriasis, as well as multiple sclerosis (MS). Researchers studying the compound DHODH, designed and produced acrylamide-based novel DHODH inhibitors as a potential treatment agents for Rheumatoid Arthritis.

Researchers identified 2-Acrylamidobenzoic acid analog 11 as the lead compound with respect to SAR studies aka Structure activity relationship studies. While the compound 54 was found to be the most potent in the study as it displayed certain favorable pharmacokinetic profiles. The compound 54 also showcased certain in vivo anti-arthritic effects in a dose-dependent manner.

The replacement of phenyl group with napthyl moieties showed improved inhibitory activity to a double digit nanomolar range. Meanwhile the structural optimization revealed that the 2-position was preferred for an acrylamide compound consisting of small hydrophobic groups such as Me, Cl, or Br. It was also observed that adding a fluoro atom at the 5-position of benzoic acid increased the potency of the compound. The optimization experiments resulted in potent compounds such as 42, 53, 54, and 55 with IC50 values of 41, 44, 32 and 42 nmol/L. These were few of the highlighting points of the study where a series of acrylamide-based novel DHODH inhibitors were developed so as to serve as a potential agent for RA treatment.