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1.
J Med Chem ; 44(18): 2933-49, 2001 Aug 30.
Article in English | MEDLINE | ID: mdl-11520202

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.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Lactams/chemical synthesis , Nitriles/chemical synthesis , Pyrrolidinones/chemical synthesis , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Binding, Competitive , Biological Availability , Cell Line, Transformed , Dogs , Drug Design , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Genes, ras , Imidazoles/chemistry , Imidazoles/pharmacology , Lactams/chemistry , Lactams/pharmacology , Mice , Mice, Transgenic , Models, Molecular , Neoplasms, Experimental/pathology , Nitriles/chemistry , Nitriles/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Radioligand Assay , Stereoisomerism , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 11(14): 1817-21, 2001 Jul 23.
Article in English | MEDLINE | ID: mdl-11459639

ABSTRACT

A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.


Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Alkyl and Aryl Transferases/drug effects , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/pharmacokinetics , Amino Acids/chemistry , Animals , Cells, Cultured , Dogs , Enzyme Inhibitors/chemical synthesis , Half-Life , Inhibitory Concentration 50 , Metabolic Clearance Rate/physiology , Molecular Conformation , Protein Binding/drug effects , Rats
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