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


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.


METHODS
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 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.


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.
Department of Immunology, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka-ken, Japan.
K
K
Kobayashi
A
A
Nakashima
H
H
Nagata
H
H
Nakajima
K
K
Yamaguchi
S
S
Sato
I
I
Miki
D000818:Animals; D001168:Arthritis / Q000139:chemically induced* / Q000188:drug therapy* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000276:immunology; D000090722:Dihydroorotate Dehydrogenase; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D019169:Jurkat Cells; D008099:Liver / Q000201:enzymology; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D015431:Weight Loss; D011798:Quinaldines
D001323:Autoantibodies; D001713:Biphenyl Compounds; D003094:Collagen; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C118187:KF 20444; C046943:brequinar; D011798:Quinaldines