title: Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: a new class of KDR kinase inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
authors.forename: Mark E
authors.initials: ME
authors.lastname: Fraley
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Robert S
authors.initials: RS
authors.lastname: Rubino
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Ruth Z
authors.initials: RZ
authors.lastname: Rutledge
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: William R
authors.initials: WR
authors.lastname: Huckle
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kendall
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
mesh_terms: D016228:Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008222:Lymphokines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008934:Mitogens / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*; D042442:Vascular Endothelial Growth Factors
chemical_list: D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D008934:Mitogens; D011720:Pyrazoles; D011743:Pyrimidines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D040301:Vascular Endothelial Growth Factor Receptor-2