Download MendeleyDiscovery of S-[5-Amino-1-(4-fluorophenyl)-1H-pyrazol-4-yl]-[3-(2,3-dihydroxypropoxy)phenyl]-methanone (RO3201195), and Orally Bioavailable and Highly Selective Inhibitor of p38 Map Kinase
Goldstein, D.M., Alfredson, T.A., Bertrand, J., Browner, M.F., Clifford, K., Dalrymple, S., Dunn, J., Freire-Moare, J., Harris, S.F., Labadie, S.S., La Fargue, J., Lapierre, J.M., Larrabee, S., Li, F., Papp, E., McWeeney, D., Ramesha, C., Roberts, R., Rotstein, D., San Pablo, B., Sjogren, E., So, O.Y., Talamas, F.X., Tao, W., Trejo, A., Villasenor, A., Welch, M., Welch, T., Weller, P., Whiteley, P.E., Young, K., Zipfel, S.(2006) J Med Chem 49: 1562-1575
- PubMed: 16509574
- DOI: https://doi.org/10.1021/jm050736c
- Primary Citation of Related Structures:
2GFS - PubMed 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.
Organizational Affiliation:
Roche Palo Alto LLC, 3431 Hillview Avenue, R6-123, Palo Alto, California 94304, USA. [email protected]
