ABSTRACT
Imidazolemethyl diaryl ethers are potent inhibitors of farnesyl-protein transferase. The SNAr displacement reaction used to prepare these diaryl ethers was amenable to rapid parallel synthesis of FPTase inhibitors. The use of a broad range of commercially available phenols quickly identified compounds which proved active in cells.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Phenyl Ethers/pharmacology , Alkyl and Aryl Transferases/metabolism , Animals , Binding, Competitive , Cell Line , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Imidazoles/chemistry , Inhibitory Concentration 50 , Peptide Library , Phenyl Ethers/chemical synthesis , Rats , Structure-Activity RelationshipSubject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Piperazines/chemical synthesis , Animals , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Humans , Imidazoles/pharmacology , Mice , Mice, Nude , Models, Molecular , Piperazines/pharmacology , Rats , Tumor Cells, CulturedABSTRACT
The design and syntheses of non-thiol inhibitors of farnesyl-protein transferase are described. Substitutions on an imidazolylmethyl-AMBA-methionine template gave a highly potent and cell-active inhibitor.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Benzamides/chemistry , Benzamides/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Alkyl and Aryl Transferases/chemistry , Alkyl and Aryl Transferases/metabolism , Animals , Benzamides/metabolism , Binding Sites , Cell Division/drug effects , Drug Design , Drug Evaluation, Preclinical , Imidazoles/chemistry , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Conformation , Rats , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , Sulfhydryl Compounds/pharmacologySubject(s)
Alkyl and Aryl Transferases , Antineoplastic Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Piperazines/chemical synthesis , Piperazines/pharmacology , Transferases/antagonists & inhibitors , Animals , Antineoplastic Agents/pharmacology , Cell Death/drug effects , Cell Division/drug effects , Cell Line, Transformed , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Farnesyltranstransferase , Mice , Mice, Nude , Molecular Conformation , Molecular Structure , Neoplasm Transplantation , Polyisoprenyl Phosphates/metabolism , Protein Prenylation , Protein Processing, Post-Translational/drug effects , Rats , Sarcoma, Experimental/drug therapy , Sarcoma, Experimental/pathology , Sesquiterpenes , ras Proteins/metabolismABSTRACT
A series of highly potent, structurally novel, non-nucleoside RT inhibitors has been described. Low nanomolar concentrations of 5-chloro-3-(phenylsulfonyl)-indole-2-carboxamide (1) inhibit the HIV-1 RT enzyme in vitro and HTLVIIIb viral spread in MT-4 human T-lymphoid cells. Good oral bioavailability was observed in rhesus monkeys upon oral dosing of 1 as a suspension in methocel. When compared to other non-nucleoside inhibitors (e.g. 15-18), 1 possesses improved inhibitory potency with respect to the wild-type RT, as well as the K103N and Y181C mutant enzymes. Additional studies within this class of inhibitors are in progress.
Subject(s)
Antiviral Agents/pharmacology , HIV-1/enzymology , Indoles/pharmacology , Reverse Transcriptase Inhibitors , Sulfoxides/pharmacology , Animals , Antiviral Agents/chemistry , Base Sequence , Biological Availability , HIV/drug effects , HIV Reverse Transcriptase , Indoles/chemistry , Indoles/pharmacokinetics , Macaca mulatta , Molecular Sequence Data , Molecular Structure , Sulfoxides/chemistry , Sulfoxides/pharmacokineticsABSTRACT
In an ongoing effort to develop novel nonnucleoside, specific human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitors, a series of 3-[(pyridylmethyl)amino]- and 3-[(phenylmethyl)amino]-2-pyridinone derivatives was synthesized and tested for HIV-1 RT inhibitory activity. The more potent compounds have a 2'-methoxy group and 4'- and/or 5'-aliphatic substituents on the pyridyl and phenyl rings. Several of the more potent compounds were also evaluated for antiviral activity in MT-4 cell culture. From this series of compounds, 3-[N-[(5-ethyl-2-methoxy-6-methyl-3-pyridyl)methyl]amino]-5-ethyl-6- methylpyridin-2(1H)-one (6) was selected for clinical evaluation.
