Abstract
A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / pharmacokinetics
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Anti-HIV Agents / pharmacology
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Cell Line
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Dogs
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Drug Resistance, Viral
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism*
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Haplorhini
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Hepatocytes / metabolism
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Humans
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Indoles / chemical synthesis*
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Indoles / pharmacokinetics
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Indoles / pharmacology
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Models, Molecular
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Mutation
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Phosphinic Acids / chemical synthesis*
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Phosphinic Acids / pharmacokinetics
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Phosphinic Acids / pharmacology
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Rats
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Reverse Transcriptase Inhibitors / chemical synthesis*
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Reverse Transcriptase Inhibitors / pharmacokinetics
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Reverse Transcriptase Inhibitors / pharmacology
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Solubility
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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Indoles
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Phosphinic Acids
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Reverse Transcriptase Inhibitors
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methyl 2-(aminocarbonyl)-5-chloro-1H-indol-3-yl-(phenyl)phosphinate
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HIV Reverse Transcriptase