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.
Choquette
Deborah
D
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. dchoquet@amgen.com
Teffera
Yohannes
Y
Polverino
Anthony
A
Harmange
Jean-Christophe
JC
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