Anti-arthritic effects of KF20444, a new immunosuppressive compound inhibiting dihydroorotate dehydrogenase, on rat collagen-induced arthritis.

Abstract

A newly synthesized inhibitor of pyrimidine de novo biosynthesis, KF20444 (6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H-benzo [6,7] cyclohepta [1,2-b] quinoline-8-carboxylic acid), was evaluated as an inhibitor of dihydroorotate dehydrogenase (DHO-DHase) and tested in the rat collagen-induced arthritis (CIA) model. Female Sprague Dawley rats, 5 weeks-old, were used for evaluation of KF20444 in the CIA model. Arthritis was evaluated by arthritis score, serum anti-type II collagen antibody titer, body weight loss, radiographical and histological changes. KF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day). KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with Ki = 8.5 +/- 3.2 nM, which was a comparable effect to that of brequinar sodium (Ki = 25.3 +/- 5.3 nM). The anti-proliferative effect of KF20444 was caused by cell cycle arrest at the S-phase. Treatment with 3 mg/kg/day of KF20444 completely prevented the development of CIA based on reduction of the arthritis score. The 50% effective dose (ED50) of KF20444 on arthritis score was 0.64 mg/kg. KF20444 ameliorated body weight loss associated with disease onset. The compound also inhibited the increase in serum anti-type II collagen antibody level, and reduced both pannus formation and bone erosion. Importantly, KF20444 suppressed the development of arthritis, even when it was administered after booster immunization of collagen. KF20444 is a novel immunosuppressant which inhibits DHO-DHase and its effects in CIA suggest that it could be useful in the treatment of rheumatoid arthritis.