Evaluation of indazole-based compounds as a new class of potent KDR/VEGFR-2 inhibitors

David Bauer; Douglas A Whittington; Angela Coxon; James Bready; Shawn P Harriman; Vinod F Patel; Anthony Polverino; Jean-Christophe Harmange

doi:10.1016/j.bmcl.2008.07.080

Evaluation of indazole-based compounds as a new class of potent KDR/VEGFR-2 inhibitors

Bioorg Med Chem Lett. 2008 Sep 1;18(17):4844-8. doi: 10.1016/j.bmcl.2008.07.080. Epub 2008 Jul 24.

Authors

David Bauer¹, Douglas A Whittington, Angela Coxon, James Bready, Shawn P Harriman, Vinod F Patel, Anthony Polverino, Jean-Christophe Harmange

Affiliation

¹ Department of Medicinal Chemistry, Amgen, Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA.

PMID: 18682324
DOI: 10.1016/j.bmcl.2008.07.080

Abstract

A novel class of potent and selective inhibitors of KDR incorporating an indazole moiety 1 is reported. The discovery, synthesis, and structure-activity relationships of this series of inhibitors have been investigated. The most promising compounds were also profiled to determine their pharmacokinetic properties and evaluated in a VEGF-induced vascular permeability assay.

Publication types

Comparative Study

MeSH terms

Animals
Capillary Permeability / drug effects
Cells, Cultured
Crystallography, X-Ray
Drug Evaluation, Preclinical
Humans
Indazoles / chemical synthesis
Indazoles / chemistry
Indazoles / metabolism
Indazoles / pharmacology*
Male
Mice
Mice, Nude
Protein Binding / physiology
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / classification
Protein Kinase Inhibitors / pharmacology*
Rats
Rats, Sprague-Dawley
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Indazoles
Protein Kinase Inhibitors
Vascular Endothelial Growth Factor Receptor-2