Synthesis and Initial SAR Studies of 3,6-Disubstituted Pyrazolo[1,5- a]pyrimidines: A New Class of KDR Kinase Inhibitors

Graphic We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5- a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2002-10, Vol.12 (19), p.2767-2770
Hauptverfasser:	Fraley, Mark E., Hoffman, William F., Rubino, Robert S., Hungate, Randall W., Tebben, Andrew J., Rutledge, Ruth Z., McFall, Rosemary C., Huckle, William R., Kendall, Richard L., Coll, Kathleen E., Thomas, Kenneth A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Antineoplastic agents Biological and medical sciences Endothelial Growth Factors - antagonists & inhibitors Endothelial Growth Factors - pharmacology Endothelium, Vascular - cytology Endothelium, Vascular - drug effects Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacology General aspects Humans Intercellular Signaling Peptides and Proteins - pharmacology Lymphokines - antagonists & inhibitors Lymphokines - pharmacology Medical sciences Mitogens - antagonists & inhibitors Mitogens - pharmacology Pharmacology. Drug treatments Pyrazoles - chemical synthesis Pyrazoles - pharmacology Pyrimidines - chemical synthesis Pyrimidines - pharmacology Structure-Activity Relationship Vascular Endothelial Growth Factor A Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factors
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Zusammenfassung:	Graphic We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5- a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions ( 3g, KDR IC 50=19 nM), respectively. The synthesis and SAR of these compounds are described.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/S0960-894X(02)00525-5