Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.
Structural analysis of the essential binding elements of the oxindole-based kinase inhibitor (1) led to the identification of a novel class of heterocyclic-substituted pyrazolones. Knoevenagel condensation of a variety of activated methylene nucleophiles with indole or pyrrole carboxaldehydes provided a focused library of molecules, each containing elements of kinase pharmacophore probe. Initial screening for VEGFR-2 kinase inhibition eliminated several of the probes. Identification of an active pyrazolone motif and further optimization resulted in several highly potent VEGFR-2 inhibitors with cellular efficacy, anti-angiogenic activity ex vivo in rat aortic ring explant cultures, and oral anti-tumor efficacy in nude mice.
Tripathy
Rabindranath
R
Cephalon, Inc., Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com
Reiboldt
Alyssa
A
Messina
Patricia A
PA
Iqbal
Mohamed
M
Singh
Jasbir
J
Bacon
Edward R
ER
Angeles
Thelma S
TS
Yang
Shi X
SX
Albom
Mark S
MS
Robinson
Candy
C
Chang
Hong
H
Ruggeri
Bruce A
BA
Mallamo
John P
JP
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D047069:Pyrazolones / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D047069:Pyrazolones; D040301:Vascular Endothelial Growth Factor Receptor-2