Synthesis, structure-activity relationships, and pharmacokinetic properties of dihydroorotate dehydrogenase inhibitors: 2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl]propenamide and related compounds

被引：85

作者：

Kuo, EA ^{[1
]}

Hambleton, PT ^{[1
]}

Kay, DP ^{[1
]}

Evans, PL ^{[1
]}

Matharu, SS ^{[1
]}

Little, E ^{[1
]}

McDowall, N ^{[1
]}

Jones, CB ^{[1
]}

Hedgecock, CJR ^{[1
]}

Yea, CM ^{[1
]}

Chan, AWE ^{[1
]}

Hairsine, PW ^{[1
]}

Ager, IR ^{[1
]}

Tully, WR ^{[1
]}

Williamson, RA ^{[1
]}

Westwood, R ^{[1
]}

机构：

[1] HOECHST MARION ROUSSEL,SWINDON SN3 5BZ,WILTS,ENGLAND

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1996年 / 39卷 / 23期

关键词：

D O I：

10.1021/jm9604437

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The active metabolite (2) of the novel immunosuppressive agent leflunomide (1) has been shown to inhibit the enzyme dihydroorotate dehydrogenase (DHODH). This enzyme catalyzes the fourth step in de novo pyrimidine biosynthesis. A series of analogues of the active metabolite 2 have been synthesized. Their in vivo biological activity determined in rat and mouse delayed type hypersensitivity has been found to correlate well with their in vitro DHODH potency. The most promising compound (3) has shown activity in rat and mouse collagen (II)-induced arthritis models (ED(50) = 2 and 31 mg/kg, respectively) and has shown a shorter half-life in man when compared with leflunomide. Clinical studies in rheumatoid arthritis are in progress.

引用

页码：4608 / 4621

页数：14

共 36 条

[21] TRIFLUOROMETHYLATIONS AND RELATED REACTIONS IN ORGANIC-CHEMISTRY [J].