Abstract
A series of HIV protease inhibitors containing a novel (hydroxyethyl)amidosuccinoyl core has been synthesized. These peptidomimetic structures inhibit viral protease activity at low nanomolar concentrations (IC50 < 10 nM for HIV-1 protease). The inhibition constant (Ki) for inhibitor 19 was determined to be 7.5 pM against HIV-1 and 1.2 nM against HIV-2 proteases, respectively. Several compounds (19-24) inhibited HIV-1 replication in cell culture assays with 50% effective concentrations (EC50) = 3.7-35 nM. This series of inhibitors was found to exhibit poor bioavailability (< 10%) in the rat, following oral administration. The synthesis and biological properties of these compounds are discussed. In addition, an X-ray structure of one of these inhibitors (23) in complex with HIV-2 protease provides insight into the binding mode of this novel class of HIV protease inhibitors.
MeSH terms
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Administration, Oral
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Animals
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Aspartic Acid Endopeptidases / chemistry
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Aspartic Acid Endopeptidases / metabolism*
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Biological Availability
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Carbamates / chemical synthesis*
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Carbamates / pharmacokinetics
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Carbamates / pharmacology
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Crystallography, X-Ray
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HIV Core Protein p24 / biosynthesis
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HIV Protease / chemistry
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HIV Protease / metabolism*
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HIV Protease Inhibitors / chemical synthesis*
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HIV Protease Inhibitors / pharmacokinetics
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HIV Protease Inhibitors / pharmacology
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HIV-1 / drug effects
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HIV-1 / enzymology
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HIV-1 / physiology*
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HIV-2 / enzymology
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Kinetics
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Protein Conformation
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Valine / analogs & derivatives*
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Valine / chemical synthesis
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Valine / pharmacokinetics
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Valine / pharmacology
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Virus Replication / drug effects*
Substances
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Carbamates
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HIV Core Protein p24
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HIV Protease Inhibitors
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Aspartic Acid Endopeptidases
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HIV Protease
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p16 protease, Human immunodeficiency virus 2
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Valine