title: Optimization of the indolyl quinolinone class of KDR (VEGFR-2) kinase inhibitors: effects of 5-amido- and 5-sulphonamido-indolyl groups on pharmacokinetics and hERG binding.
abstract: Modifications to the basic side-chain of early lead structures of the indolyl quinolinone class of KDR kinase inhibitors resulted in improved pharmacokinetic and ancillary profiles. Specifically, compounds bearing 5-amido- and 5-sulphonamido-indolyl substituents exhibited lower plasma clearance and weaker binding affinity for the I(Kr) potassium channel hERG.
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: Kenneth L
authors.initials: KL
authors.lastname: Arrington
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Buser
authors.forename: Patrice A
authors.initials: PA
authors.lastname: Ciecko
authors.forename: Kathleen E
authors.initials: KE
authors.lastname: Coll
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandes
authors.forename: George D
authors.initials: GD
authors.lastname: Hartman
authors.forename: William F
authors.initials: WF
authors.lastname: Hoffman
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: McFall
authors.forename: Keith
authors.initials: K
authors.lastname: Rickert
authors.forename: Romi
authors.initials: R
authors.lastname: Singh
authors.forename: Sheri
authors.initials: S
authors.lastname: Smith
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Thomas
authors.forename: Bradley K
authors.initials: BK
authors.lastname: Wong
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D051638:Ether-A-Go-Go Potassium Channels; D006801:Humans; D008862:Microsomes, Liver / Q000201:enzymology; D015221:Potassium Channels / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011485:Protein Binding / Q000502:physiology; D015363:Quinolones / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D027682:Cation Transport Proteins; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015363:Quinolones; D040301:Vascular Endothelial Growth Factor Receptor-2