Abstract
Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.
MeSH terms
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Administration, Oral
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Animals
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Biological Availability
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COS Cells
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Cell Division / drug effects
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Haplorhini
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Mice
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Mice, Nude
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Protein Prenylation
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Proto-Oncogene Proteins p21(ras) / metabolism
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacokinetics
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Sulfonylurea Compounds / chemical synthesis*
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Sulfonylurea Compounds / chemistry
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Sulfonylurea Compounds / pharmacokinetics
Substances
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Enzyme Inhibitors
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Piperidines
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Pyridines
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Sulfonamides
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Sulfonylurea Compounds
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Alkyl and Aryl Transferases
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p21(ras) farnesyl-protein transferase
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Proto-Oncogene Proteins p21(ras)
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lonafarnib