N-Phenyl-N-purin-6-yl ureas: the design and synthesis of p38alpha MAP kinase inhibitors

The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38alpha kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38alpha kinase, which...

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Published inBioorganic & medicinal chemistry letters Vol. 13; no. 6; pp. 1191 - 1194
Main Authors Wan, Zehong, Boehm, Jeffrey C, Bower, Michael J, Kassis, Shouki, Lee, John C, Zhao, Baoguang, Adams, Jerry L
Format Journal Article
LanguageEnglish
Published England 24.03.2003
Subjects
Crystallography, X-Ray
Drug Design
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - pharmacology
Indicators and Reagents
Magnetic Resonance Spectroscopy
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Models, Molecular
Molecular Conformation
p38 Mitogen-Activated Protein Kinases
Structure-Activity Relationship
Urea - analogs & derivatives
Urea - chemical synthesis
Urea - pharmacology
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Summary:The design, synthesis and SAR of a series of 2,6,9-trisubstituted purine inhibitors of p38alpha kinase is reported. Synthetic routes were devised to allow for array synthesis in which all three points of diversity could be facilely explored. The binding of this novel series to p38alpha kinase, which was predicted to have several key interactions in common with SB-203580, was confirmed by X-ray crystallography of 19 (p38 IC(50)=82 nM).
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ISSN:0960-894X