title: 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.
abstract: 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 (ED50 = 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.
authors.affiliation: Hoechst Marion Roussel, Wiltshire, England.
authors.forename: E A
authors.initials: EA
authors.lastname: Kuo
authors.forename: P T
authors.initials: PT
authors.lastname: Hambleton
authors.forename: D P
authors.initials: DP
authors.lastname: Kay
authors.forename: P L
authors.initials: PL
authors.lastname: Evans
authors.forename: S S
authors.initials: SS
authors.lastname: Matharu
authors.forename: E
authors.initials: E
authors.lastname: Little
authors.forename: N
authors.initials: N
authors.lastname: McDowall
authors.forename: C B
authors.initials: CB
authors.lastname: Jones
authors.forename: C J
authors.initials: CJ
authors.lastname: Hedgecock
authors.forename: C M
authors.initials: CM
authors.lastname: Yea
authors.forename: A W
authors.initials: AW
authors.lastname: Chan
authors.forename: P W
authors.initials: PW
authors.lastname: Hairsine
authors.forename: I R
authors.initials: IR
authors.lastname: Ager
authors.forename: W R
authors.initials: WR
authors.lastname: Tully
authors.forename: R A
authors.initials: RA
authors.lastname: Williamson
authors.forename: R
authors.initials: R
authors.lastname: Westwood
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006968:Hypersensitivity, Delayed; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D051381:Rats; D017208:Rats, Wistar; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000178:Acrylamides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000090722:Dihydroorotate Dehydrogenase; D004791:Enzyme Inhibitors; C102320:2-cyano-3-cyclopropyl-3-hydroxy-N-(3'-methyl-4'-(trifluoromethyl)phenyl)propenamide; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors