Abstract
Replacement of the pyridylmethyl moiety in indinavir with a pyridyl oxazole yielded HIV-1 protease inhibitors (PI) with greatly improved potency against PI-resistant HIV-1 strains. A meta-methoxy group on the pyridyl ring and a gem-dimethyl methyl linkage afforded compound 10 with notable in vitro antiviral activity against HIV-1 viral strains with reduced susceptibility to the clinically available PIs. Compound 10 also demonstrated favorable in vivo pharmacokinetics in animal models.
MeSH terms
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Animals
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Biological Availability
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Cell Line
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Dogs
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Drug Resistance, Viral*
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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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Humans
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In Vitro Techniques
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Indinavir / pharmacokinetics
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Indinavir / pharmacology
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Macaca mulatta
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Microsomes, Liver / metabolism
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Rats
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T-Lymphocytes / drug effects
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T-Lymphocytes / virology
Substances
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Cytochrome P-450 Enzyme Inhibitors
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HIV Protease Inhibitors
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Indinavir
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CYP3A protein, human
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Cytochrome P-450 CYP3A