The discovery of N-(1,3-thiazol-2-yl)pyridin-2-amines as potent inhibitors of KDR kinase.
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Bilodeau
Mark T
MT
Departments of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. mark_bilodeau@merck.com
Rodman
Leonard D
LD
McGaughey
Georgia B
GB
Coll
Kathleen E
KE
Koester
Timothy J
TJ
Hoffman
William F
WF
Hungate
Randall W
RW
Kendall
Richard L
RL
McFall
Rosemary C
RC
Rickert
Keith W
KW
Rutledge
Ruth Z
RZ
Thomas
Kenneth A
KA
D000588:Amines / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000588:Amines; D004791:Enzyme Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2