The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-arthritic efficacy

Bioorg Med Chem. 2001 Feb;9(2):537-54. doi: 10.1016/s0968-0896(00)00331-x.


RPR132331, a 2-(2-dioxanyl)imidazole, was identified as an inhibitor of tumour necrosis factor (TNF)alpha release from lipopolysaccharide (LPS)-stimulated human monocytes. An intensive programme of work exploring the biology, toxicity and physical chemistry of a novel series of inhibitors, derived from RPR132331, has led to the identification of RPR200765A, a development candidate for the treatment of rheumatoid arthritis (RA). RPR200765A is a potent and selective inhibitor of p38 MAP kinase (IC50 = 50 nM). It inhibits LPS-stimulated TNFalpha release both in vitro, from human monocytes (EC50 = 110 nM), and in vivo in Balb/c mice (ED50 = 6 mg/kg). At oral doses between 10 and 30 mg/kg/day it reduces the incidence and progression in the rat streptococcal cell wall (SCW) arthritis model when administered in either prophylactic or therapeutic dosing regimens. The compound, which is a mesylate salt and exists as a stable monohydrate, shows good oral bioavailabiltiy (F = 50% in the rat) and excellent chemical stability. The data from the SCW disease model suggests that RPR200765A could exhibit a profile of disease modifying activity in rheumatoid arthritis (RA) patients which is not observed with current drug therapies.

MeSH terms

  • Administration, Oral
  • Animals
  • Antirheumatic Agents / chemical synthesis*
  • Antirheumatic Agents / pharmacokinetics*
  • Antirheumatic Agents / pharmacology
  • Arthritis / chemically induced
  • Arthritis / drug therapy
  • Arthritis / prevention & control
  • Biological Availability
  • Cytochrome P-450 CYP1A1 / drug effects
  • Cytochrome P-450 CYP1A1 / metabolism
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Enzyme Induction / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Female
  • Humans
  • Imidazoles / chemical synthesis
  • Imidazoles / pharmacology*
  • Inhibitory Concentration 50
  • Lipopolysaccharides / pharmacology
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • Monocytes / drug effects
  • Monocytes / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / drug effects
  • p38 Mitogen-Activated Protein Kinases


  • Antirheumatic Agents
  • Enzyme Inhibitors
  • Imidazoles
  • Lipopolysaccharides
  • RPR 200765A
  • Tumor Necrosis Factor-alpha
  • Cytochrome P-450 CYP1A1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases