Abstract
Variously substituted indolin-2-ones were synthesized and evaluated for activity against KDR, Flt-1, FGFR-1 and PDGFR. Extension at the 5-position of the oxindole ring with ethyl piperidine (compound 7i) proved to be the most beneficial for attaining both biochemical and cellular potencies. Further optimization of 7i to balance biochemical and cellular potencies with favorable ADME/ PK properties led to the identification of 8h, a compound with a clean CYP profile, acceptable pharmacokinetic and toxicity profiles, and robust efficacy in multiple xenograft tumor models.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Cytochrome P-450 CYP3A / metabolism
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Drug Design*
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Female
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Half-Life
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / therapeutic use
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Lung / drug effects
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Lung / metabolism
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Mice
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Neoplasms / drug therapy
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / therapeutic use
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacokinetics
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Protein Kinase Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Rats
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
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Receptor Protein-Tyrosine Kinases / metabolism
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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3-((4-chlorophenyl)(1H-imidazol-2-yl)methylene)-5-(1-ethylpiperidin-4-ylamino)indolin-2-one
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Indoles
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Piperidines
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Protein Kinase Inhibitors
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CYP3A protein, human
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Cytochrome P-450 CYP3A
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Receptor Protein-Tyrosine Kinases