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.
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.
Fraley
Mark E
ME
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. mark_fraley@merck.com
Arrington
Kenneth L
KL
Buser
Carolyn A
CA
Ciecko
Patrice A
PA
Coll
Kathleen E
KE
Fernandes
Christine
C
Hartman
George D
GD
Hoffman
William F
WF
Lynch
Joseph J
JJ
McFall
Rosemary C
RC
Rickert
Keith
K
Singh
Romi
R
Smith
Sheri
S
Thomas
Kenneth A
KA
Wong
Bradley K
BK
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
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