title: Property-based design of KDR kinase inhibitors.
abstract: Small molecule inhibitors of KDR kinase activity have typically possessed poor intrinsic physical properties including low aqueous solubility and high lipophilicity. These features have often conferred limited cell permeability manifested in low levels of cell-based KDR inhibitory activity and oral bioavailability. Thus, the design of inhibitors with appropriate physical properties has played a critical role in the development of clinical candidates. We present a variety of structural modifications that have afforded improvements in physical properties and thereby have addressed suboptimal cellular potency and pharmacokinetics for three unique classes of KDR kinase inhibitors.
authors.affiliation: Departments of Medicinal Chemistry, Cancer Research and Molecular Systems, 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: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Randy W
authors.initials: RW
authors.lastname: Hungate
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
authors.forename: Georgia B
authors.initials: GB
authors.lastname: McGaughey
mesh_terms: D000818:Animals; D001665:Binding Sites; D001682:Biological Availability; D002463:Cell Membrane Permeability; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D012995:Solubility; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D040301:Vascular Endothelial Growth Factor Receptor-2