Abstract
The synthesis, structure-activity relationships, and biological properties of a novel series of imidazole-containing inhibitors of farnesyltransferase are described. Starting from a 3-aminopyrrolidinone core, a systematic series of modifications provided 5h, a non-thiol, non-peptide farnesyltransferase inhibitor with excellent bioavailability in dogs. Compound 5h was found to have an unusually favorable ratio of cell potency to intrinsic potency, compared with other known FTIs. It exhibited excellent potency against a range of tumor cell lines in vitro and showed full efficacy in the K-rasB transgenic mouse model.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Binding Sites
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Binding, Competitive
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Biological Availability
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Cell Line, Transformed
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Dogs
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Drug Design
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Drug Screening Assays, Antitumor
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Farnesyltranstransferase
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Genes, ras
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Imidazoles / chemical synthesis*
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Imidazoles / chemistry
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Imidazoles / pharmacology
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Lactams / chemical synthesis*
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Lactams / chemistry
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Lactams / pharmacology
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Mice
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Mice, Transgenic
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Models, Molecular
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Neoplasms, Experimental / pathology
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Nitriles / chemical synthesis*
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Nitriles / chemistry
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Nitriles / pharmacology
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Pyrrolidinones / chemical synthesis*
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacology
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Radioligand Assay
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Stereoisomerism
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Structure-Activity Relationship
Substances
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4-(5-((1-(3-chlorobenzyl)-2-oxopyrrolidin-3-ylamino)methyl)imidazol-1-ylmethyl)benzonitrile
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Antineoplastic Agents
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Enzyme Inhibitors
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Imidazoles
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Lactams
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Nitriles
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Pyrrolidinones
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Alkyl and Aryl Transferases
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Farnesyltranstransferase