Abstract
A systematic investigation was undertaken to determine the role of the P1' sidechain in a series of hydroxyethylene isostere based inhibitors of HIV-1 protease. Substitution and homologation of the benzyl P1' side chain of the Phe-Phe isostere based pseudo peptides 1 (L-682,679) and 2 (L-685,434) with various heteroalkyl groups leads to a series of extremely potent inhibitors of the enzyme. Several examples of the most potent inhibitors were very effective in an ex vivo cell based viral spread assay using human H9 T-lymphocytes and the IIIb isolate of HIV-1. Compound 19 is 120 times more potent than 1 and 16 times more potent than 2 in inhibiting the spread of infection in this assay.
MeSH terms
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Antiviral Agents / chemistry
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Antiviral Agents / pharmacology*
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Dipeptides / chemical synthesis
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Dipeptides / chemistry
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Dipeptides / pharmacology*
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Ethylenes / chemical synthesis
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Ethylenes / pharmacology*
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HIV Protease / metabolism
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HIV Protease Inhibitors*
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HIV-1 / enzymology*
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HIV-1 / growth & development
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Humans
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Indoles / chemistry
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Indoles / pharmacology
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Phosphates / chemistry
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology
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Solubility
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Structure-Activity Relationship
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T-Lymphocytes / microbiology
Substances
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Antiviral Agents
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Dipeptides
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Ethylenes
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HIV Protease Inhibitors
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Indoles
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Oligopeptides
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Phosphates
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Protease Inhibitors
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L 682679
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L 685434
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hydroxyethylene
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HIV Protease