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.
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.
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. dchoquet@amgen.com
Deborah
D
Choquette
Yohannes
Y
Teffera
Anthony
A
Polverino
Jean-Christophe
JC
Harmange
D000818:Animals; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification*; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000737:chemistry* / Q000302:isolation & purification*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000302:isolation & purification*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; C109853:G 1617; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D040301:Vascular Endothelial Growth Factor Receptor-2