Structure-guided identification of novel VEGFR-2 kinase inhibitors via solution phase parallel synthesis |
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Authors: | Tripathy Rabindranath Reiboldt Alyssa Messina Patricia A Iqbal Mohamed Singh Jasbir Bacon Edward R Angeles Thelma S Yang Shi X Albom Mark S Robinson Candy Chang Hong Ruggeri Bruce A Mallamo John P |
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Affiliation: | Cephalon, Inc., Discovery Research, 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com |
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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. |
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