Discovery of S-[5-amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]methanone (RO3201195), an orally bioavailable and highly selective inhibitor of p38 MAP kinase

J Med Chem. 2006 Mar 9;49(5):1562-75. doi: 10.1021/jm050736c.


A novel class of highly selective inhibitors of p38 MAP kinase was discovered from high throughput screening. The synthesis and optimization of a series of 5-amino-N-phenyl-1H-pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38alpha established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 which likely contributes to the selectivity for p38. The crystallographic information was used to optimize the potency and physicochemical properties of the series. The incorporation of the 2,3-dihydroxypropoxy moiety on the pyrazole scaffold resulted in a compound with excellent drug-like properties including high oral bioavailability. These efforts identified 63 (RO3201195) as an orally bioavailable and highly selective inhibitor of p38 which was selected for advancement into Phase I clinical trials.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Arthritis, Experimental / drug therapy
  • Binding Sites
  • Biological Availability
  • Cell Line
  • Crystallography, X-Ray
  • Dogs
  • Female
  • Haplorhini
  • Humans
  • Interleukin-1 / antagonists & inhibitors
  • Interleukin-1 / biosynthesis
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / biosynthesis
  • Models, Molecular
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Rats
  • Rats, Inbred Lew
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • p38 Mitogen-Activated Protein Kinases / chemistry


  • 5-amino-1-(4-fluorophenyl)-4-(3-(2,3-dihydroxypropoxy)benzoyl)pyrazole
  • Anti-Inflammatory Agents
  • Interleukin-1
  • Interleukin-6
  • Pyrazoles
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases