Abstract
HIV-1 protease inhibitors (PI) with an N-arylpyrrole moiety in the P(3) position afforded excellent antiviral potency and substantially improved aqueous solubility over previously reported variants. The rapid in vitro clearance of these compounds in human liver microsomes prompted oral coadministration with indinavir to hinder their metabolism by the cyctochrome P450 3A4 isozyme and allow for in vivo PK assessment.
MeSH terms
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Acquired Immunodeficiency Syndrome / drug therapy
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Administration, Oral
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Biotransformation
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Cytochrome P-450 CYP2D6 / metabolism
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / metabolism
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Drug Design
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Drug Resistance, Viral
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Drug Therapy, Combination
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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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Humans
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Indinavir / pharmacology
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Indinavir / therapeutic use*
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Pyrroles / chemical synthesis
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Pyrroles / pharmacology
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Structure-Activity Relationship
Substances
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HIV Protease Inhibitors
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Pyrroles
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Indinavir
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Cytochrome P-450 Enzyme System
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CYP3A protein, human
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Cytochrome P-450 CYP2D6
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Cytochrome P-450 CYP3A
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HIV Protease