ABSTRACT
Replacement of the central amino methylene linkage of C[psi CH2NH]A[psi CH2NH]AX tetrapeptide inhibitors with carbon tethers led to compounds with potency in the nanomolar range. Some of the more potent olefinic compounds inhibit Ras processing in intact v-ras transformed NIH 3T3 cells with IC50 values in the 0.1 to 1 microM range, and inhibit selectively the anchorage-independent growth of H-ras transformed Rat1 cells at 10 microM.
Subject(s)
Alkyl and Aryl Transferases , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Transferases/antagonists & inhibitors , 3T3 Cells , Amino Acid Sequence , Animals , Cell Transformation, Viral , Genes, ras , Mice , Molecular Sequence Data , Molecular Structure , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A new series of potent specific 2-pyridinone reverse transcriptase (RT) inhibitors was developed based on the preliminary development lead 3-[(phthalmido)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (3), a non-nucleoside derivative which exhibited weak antiviral activity in cell culture against HIV-1 strain IIIB. One compound, 3-[(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (9,L-696,229), which was a highly selective antagonist of the RT enzyme (IC50 = 23 nM) and which inhibited the spread of HIV-1 IIIB infection by > 95% in MT4 human T-lymphoid cell culture (CIC95 = 50-100 nM), was selected for clinical evaluation as an antiviral agent.
Subject(s)
Antiviral Agents/chemical synthesis , Benzoxazoles/chemical synthesis , Pyridones/chemical synthesis , Reverse Transcriptase Inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Blood Proteins/metabolism , Cells, Cultured , Drug Evaluation , HIV Reverse Transcriptase , Humans , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Aminopyridines/chemical synthesis , Antiviral Agents/chemical synthesis , Pyridones/chemical synthesis , Reverse Transcriptase Inhibitors , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cells, Cultured , HIV Reverse Transcriptase , Haplorhini , Pyridones/chemistry , Pyridones/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
A series of nonnucleoside 3-aminopyridin-2(1H)-one derivatives was synthesized and evaluated for HIV-1 RT inhibitory properties. Several analogs proved to be potent and highly selective antagonists with in vitro IC50 values as low as 19 nM in the enzyme assay using rC.dG as template-primer. Two compounds from this series, 3-[[(4,7-dimethylbenzoxazol-2-yl)methyl]-amino]-5-ethyl-6-methy lpyridin-2(1H)-one (34, L-697,639) and the corresponding 4,7-dichloro analogue (37, L-697,661) inhibited the spread of HIV-1 IIIb infection by 95% in MT4 cell culture at concentrations of 25-50 nM and were selected for clinical trials as antiviral agents.
