Isoindolinone ureas: a novel class of KDR kinase inhibitors.
A series of substituted isoindolinone ureas was prepared and evaluated for enzymatic and cellular inhibition of KDR kinase activity. Several of these analogs, such as 14c, are potent inhibitors of KDR both enzymatically (< 50 nM) and cellularly < or = 100 nM). A 3D KDR/CDK2/MAP kinase overlay model with several structurally related tyrosine kinase inhibitors was used to predict the binding interactions of the isoindolinone ureas with the KDR active site.
Curtin
Michael L
ML
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064-6100, USA. mike.curtin@abbott.com
Frey
Robin R
RR
Heyman
H Robin
HR
Sarris
Kathy A
KA
Steinman
Douglas H
DH
Holmes
James H
JH
Bousquet
Peter F
PF
Cunha
George A
GA
Moskey
Maria D
MD
Ahmed
Asma A
AA
Pease
Lori J
LJ
Glaser
Keith B
KB
Stewart
Kent D
KD
Davidsen
Steven K
SK
Michaelides
Michael R
MR
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D041681:NIH 3T3 Cells; D014508:Urea / Q000737:chemistry* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D007211:Indoles; D014508:Urea; D040301:Vascular Endothelial Growth Factor Receptor-2