2. Academic Validation
  3. 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

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.
David M Goldstein 1,  Tom Alfredson,  Jay Bertrand,  Michelle F Browner,  Ken Clifford,  Stacie A Dalrymple,  James Dunn,  Jose Freire-Moar,  Seth Harris,  Sharada S Labadie,  JoAnn La Fargue,  Jean Marc Lapierre,  Susan Larrabee,  Fujun Li,  Eva Papp,  Daniel McWeeney,  Chakk Ramesha,  Rick Roberts,  David Rotstein,  Bong San Pablo,  Eric B Sjogren,  On-Yee So,  Francisco X Talamas,  Will Tao,  Alejandra Trejo,  Armando Villasenor,  Mary Welch,  Teresa Welch,  Paul Weller,  Phyllis E Whiteley,  Kelly Young,  Sheila Zipfel
Affiliations

Affiliation

  • 1 Roche Palo Alto LLC, 3431 Hillview Avenue, R6-123, Palo Alto, California 94304, USA. [email protected]
PMID: 16509574 DOI: 10.1021/jm050736c
Abstract

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.

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