Abstract
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Keywords:
FPT inhibitors.
Copyright © 2013 Elsevier Ltd. All rights reserved.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / metabolism
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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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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crystallography, X-Ray
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Dogs
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Dose-Response Relationship, Drug
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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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Haplorhini
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Humans
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Mice
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Mice, Transgenic
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Models, Molecular
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Molecular Structure
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Neoplasms, Experimental / drug therapy*
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Neoplasms, Experimental / pathology
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Rats
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Structure-Activity Relationship
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Aza Compounds
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Enzyme Inhibitors
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Pyridines
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Alkyl and Aryl Transferases
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p21(ras) farnesyl-protein transferase