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

J Med Chem. 1996 Nov 8;39(23):4608-21. doi: 10.1021/jm9604437.

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.

MeSH terms

  • Acrylamides / chemical synthesis*
  • Acrylamides / pharmacokinetics
  • Acrylamides / therapeutic use
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Arthritis, Experimental / drug therapy
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Hypersensitivity, Delayed
  • Kinetics
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Mice, Inbred DBA
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Rats
  • Rats, Wistar
  • Spectrophotometry, Infrared
  • Structure-Activity Relationship

Substances

  • Acrylamides
  • Anti-Inflammatory Agents, Non-Steroidal
  • Enzyme Inhibitors
  • 2-cyano-3-cyclopropyl-3-hydroxy-N-(3'-methyl-4'-(trifluoromethyl)phenyl)propenamide
  • Oxidoreductases
  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase