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 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).
Wan
Zehong
Z
Department of Medicinal Chemistry, Respiratory and Inflammation CEDD, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, PO Box 1539, King of Prussia, PA 19406, USA. zehong_2_wan.gsk.com
Boehm
Jeffrey C
JC
Bower
Michael J
MJ
Kassis
Shouki
S
Lee
John C
JC
Zhao
Baoguang
B
Adams
Jerry L
JL
D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; C478084:N-phenyl-N-purin-6-yl urea; D014508:Urea; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases