RO4383596, an orally active KDR, FGFR, and PDGFR inhibitor: synthesis and biological evaluation.
(+/-)-1-(anti-3-Hydroxy-cyclopentyl)-3-(4-methoxy-phenyl)-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (RO4383596) is a potent and selective inhibitor of the pro-angiogenic receptor tyrosine kinases KDR, FGFR, and PDGFR. This agent has an excellent pharmacokinetic profile and is highly efficacious in rodent models of angiogenesis upon oral administration.
McDermott
Lee A
LA
Hoffmann-La Roche Inc., 340 Kingsland Str., Nutley, NJ 07110, USA. lee.mcdermott@roche.com
Simcox
Mary
M
Higgins
Brian
B
Nevins
Tom
T
Kolinsky
Kenneth
K
Smith
Melissa
M
Yang
Hong
H
Li
Jia K
JK
Chen
Yingsi
Y
Ke
June
J
Mallalieu
Navita
N
Egan
Tom
T
Kolis
Stan
S
Railkar
Aruna
A
Gerber
Louise
L
Luk
Kin-Chun
KC
D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016510:Corneal Neovascularization / Q000188:drug therapy; D005260:Female; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors
D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011744:Pyrimidinones; C506187:RO4383596; D017468:Receptors, Fibroblast Growth Factor; D011505:Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2