title: Optimization of a pyrazolo[1,5-a]pyrimidine class of KDR kinase inhibitors: improvements in physical properties enhance cellular activity and pharmacokinetics.
abstract: We have introduced solubilizing functionality to a 3,6-disubstituted pyrazolo[1,5-a]pyrimidine series of KDR kinase inhibitors to improve the physical properties of these compounds. The addition of a basic side-chain to the 6-aryl ring, introduction of 3-pyridyl groups, and most significantly, incorporation of a 4-pyridinonyl substituent at the 6-position of the core are modifications that maintain and often enhance the intrinsic potency of this class of inhibitors. Moreover, the improvements in physical properties result in marked increases in cellular activity and more favorable pharmacokinetics in rats. 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: Robert S
authors.initials: RS
authors.lastname: Rubino
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Scott R
authors.initials: SR
authors.lastname: Hambaugh
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Randall W
authors.initials: RW
authors.lastname: Hungate
authors.forename: Mark T
authors.initials: MT
authors.lastname: Bilodeau
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Tebben
authors.forename: Ruth Z
authors.initials: RZ
authors.lastname: Rutledge
authors.forename: Richard L
authors.initials: RL
authors.lastname: Kendall
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: William R
authors.initials: WR
authors.lastname: Huckle
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D004791:Enzyme Inhibitors; D011743:Pyrimidines; D040301:Vascular Endothelial Growth Factor Receptor-2