title: Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis.
abstract: 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.
authors.affiliation: Cephalon, Inc., Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Tripathy
authors.forename: Alyssa
authors.initials: A
authors.lastname: Reiboldt
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Messina
authors.forename: Mohamed
authors.initials: M
authors.lastname: Iqbal
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
authors.forename: Edward R
authors.initials: ER
authors.lastname: Bacon
authors.forename: Thelma S
authors.initials: TS
authors.lastname: Angeles
authors.forename: Shi X
authors.initials: SX
authors.lastname: Yang
authors.forename: Mark S
authors.initials: MS
authors.lastname: Albom
authors.forename: Candy
authors.initials: C
authors.lastname: Robinson
authors.forename: Hong
authors.initials: H
authors.lastname: Chang
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Ruggeri
authors.forename: John P
authors.initials: JP
authors.lastname: Mallamo
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D047069:Pyrazolones; D040301:Vascular Endothelial Growth Factor Receptor-2