Discovery of novel 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones as potent and selective inhibitors of KDR: synthesis, SAR, and pharmacokinetic properties

Deborah Choquette; Yohannes Teffera; Anthony Polverino; Jean-Christophe Harmange

doi:10.1016/j.bmcl.2008.05.114

Discovery of novel 1,2,3,4-tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones as potent and selective inhibitors of KDR: synthesis, SAR, and pharmacokinetic properties

Bioorg Med Chem Lett. 2008 Jul 15;18(14):4054-8. doi: 10.1016/j.bmcl.2008.05.114. Epub 2008 Jun 4.

Authors

Deborah Choquette¹, Yohannes Teffera, Anthony Polverino, Jean-Christophe Harmange

Affiliation

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

PMID: 18573658
DOI: 10.1016/j.bmcl.2008.05.114

Abstract

1,2,3,4-Tetrahydroisoquinolines and 3,4-dihydroisoquinoline-1(2H)-ones were identified as potent and selective inhibitors of KDR. The discovery, synthesis, and structure-activity relationships of these novel inhibitors are reported. In vitro metabolism and pharmacokinetic profiles of the most interesting compounds are discussed.

MeSH terms

Animals
Cell Line
Chemistry, Pharmaceutical / methods
Drug Design
Endothelium, Vascular / cytology
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / isolation & purification*
Humans
Inhibitory Concentration 50
Isoquinolines / chemistry*
Isoquinolines / isolation & purification*
Male
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / isolation & purification*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*

Substances

Enzyme Inhibitors
G 1617
Isoquinolines
Tetrahydroisoquinolines
Vascular Endothelial Growth Factor Receptor-2