Abstract
Mechanistic information and structure-based design methods have been used to design a series of nonpeptide cyclic ureas that are potent inhibitors of human immunodeficiency virus (HIV) protease and HIV replication. A fundamental feature of these inhibitors is the cyclic urea carbonyl oxygen that mimics the hydrogen-bonding features of a key structural water molecule. The success of the design in both displacing and mimicking the structural water molecule was confirmed by x-ray crystallographic studies. Highly selective, preorganized inhibitors with relatively low molecular weight and high oral bioavailability were synthesized.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Azepines / chemistry*
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Azepines / metabolism
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Azepines / pharmacokinetics
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Azepines / pharmacology
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Binding Sites
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Biological Availability
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Cell Line
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Crystallography, X-Ray
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Dogs
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Drug Design*
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Drug Evaluation, Preclinical
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HIV Protease / chemistry
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HIV Protease / metabolism
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HIV Protease Inhibitors / chemistry*
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HIV Protease Inhibitors / metabolism
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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 / physiology
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Hydrogen Bonding
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Models, Molecular
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Molecular Conformation
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Molecular Weight
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Rats
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Urea
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Virus Replication / drug effects
Substances
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Azepines
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HIV Protease Inhibitors
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Recombinant Proteins
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Urea
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HIV Protease