Discovery of S-[5-Amino-1-(4-fluorophenyl)-1 H-pyrazol-4-yl]-[3-(2, 3-dihydroxypropoxy) phenyl] methanone (RO3201195), an Orally Bioavailable and Highly …

…, SA Dalrymple, J Dunn, J Freire-Moar…

文献索引：Goldstein, David M.; Alfredson, Tom; Bertrand, Jay; Browner, Michelle F.; Clifford, Ken; Dalrymple, Stacie A.; Dunn, James; Freire-Moar, Jose; Harris, Seth; Labadie, Sharada S.; La Fargue, JoAnn; Lapierre, Jean Marc; Larrabee, Susan; Li, Fujun; Papp, Eva; McWeeney, Daniel; Ramesha, Chakk; Roberts, Rick; Rotstein, David; San Pablo, Bong; Sjogren, Eric B.; So, On-Yee; Talamas, Francisco X.; Tao, Will; Trejo, Alejandra; Villasenor, Armando; Welch, Mary; Welch, Teresa; Weller, Paul; Whiteley, Phyllis E.; Young, Kelly; Zipfel, Sheila Journal of Medicinal Chemistry, 2006 , vol. 49, # 5 p. 1562 - 1575

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被引用次数: 62

摘要

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-1 H- pyrazol-4-yl-3-phenylmethanones is described. An X-ray crystal structure of this series bound in the ATP binding pocket of unphosphorylated p38α established the presence of a unique hydrogen bond between the exocyclic amine of the inhibitor and threonine 106 ...