Refinements in the understanding of the mechanisms of immunocyte activation and the emergence of new immunosuppressive agents with highly selective actions has created opportunities for improving the treatment of autoimmune hepatitis. Drugs, such as budesonide and deflazacort, may inhibit immunocyte activation and limit corticosteroid-related side effects. Agents, such as cyclosporine and tacrolimus, can impair calcineurin activity and restrict the generation of transcription factors necessary for T cell responses. Intravenous immunoglobulin can bind anti-idiotype antibodies and reduce interleukin-2 secretion, and monoclonal antibodies directed against critical components of the T cell activation cascade can dampen the immune reaction. Drugs, such as mycophenolate mofetil, cyclophosphamide, methotrexate, and KF20444, can inhibit T cell proliferation, and other interventions promise to deplete activated T cells, impair effector mechanisms, and induce self-tolerance.

01 Dec 2001·Bioorganic & Medicinal ChemistryQ3 · MEDICINE

Synthetic study on novel immunosuppressant KF20444

Q3 · MEDICINE

Article

Author: Masaji Kasai ; Iwao Chujo ; Kenji Fujino ; Shin-ichiro Mohri ; Sachiko Kato ; Yoshiaki Masuda ; Takehiro Ogasa

The two new synthetic routes to 6,7-dihydro-10-fluoro-3-(2-fluorophenyl)-5H- benzo[6,7]cyclohepta[1,2-b]-quinoline-8-carboxylic acid (1), a novel immunosuppressant KF20444, are described. The seven-membered ring construction from 2-[4-(2-fluorophenyl)phenyl]-3-(2-carboxyethyl)-4-chloromethyl-6-fluoroquinoline (17c) was achieved by intramolecular Friedel-Crafts reaction under acidic conditions as the key step. Subsequently, the oxidation of 4-chloromethyl group followed by reduction of carbonyl group on the seven-membered ring afforded 1. This route provides a new method for the synthesis of 1.

01 Feb 2001·Inflammation ResearchQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: Nakashima, A. ; Yamaguchi, K. ; Nagata, H. ; Nakajima, H. ; Sato, S. ; Miki, I. ; Kobayashi, K.

OBJECTIVE AND DESIGNA 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 METHODSFemale 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.TREATMENTKF20444 was orally administered 5 times per week (0.3, 1, 3 mg/kg/day).RESULTSKF20444 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.CONCLUSIONSKF20444 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.

100 Deals associated with KF-20444

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Indication	Highest Phase	Country/Location	Organization	Date
Graft Rejection	Preclinical	Japan	Kyowa Kirin Co., Ltd.	-
Rheumatoid Arthritis	Preclinical	Japan	Kyowa Kirin Co., Ltd.	-

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