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

Abstract:

Objective and Design: 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.¶Material and Methods: 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.¶Treatment: KF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day).¶Results: KF20444 inhibited rat liver dihydroorotate dehydrogenase in vitro with K_i = 8.5 ± 3.2 nM, which was a comparable effect to that of brequinar sodium (K_i = 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.¶Conclusions: 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.¶