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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2004-01, Vol.14 (2), p.351-355
Hauptverfasser:	Fraley, Mark E., Arrington, Kenneth L., Buser, Carolyn A., Ciecko, Patrice A., Coll, Kathleen E., Fernandes, Christine, Hartman, George D., Hoffman, William F., Lynch, Joseph J., McFall, Rosemary C., Rickert, Keith, Singh, Romi, Smith, Sheri, Thomas, Kenneth A., Wong, Bradley K.
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antineoplastic agents Biological and medical sciences Cation Transport Proteins - metabolism Cell Line Dogs Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacokinetics Ether-A-Go-Go Potassium Channels General aspects Humans Medical sciences Microsomes, Liver - enzymology Pharmacology. Drug treatments Potassium Channels - metabolism Potassium Channels, Voltage-Gated Protein Binding - physiology Quinolones - chemistry Quinolones - pharmacokinetics Rats Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Vascular Endothelial Growth Factor Receptor-2 - metabolism
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Zusammenfassung:	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. ©2003 Elsevier Science Ltd. All rights reserved. Graphic
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2003.11.007