Abstract
HIV-1 integrase (IN) is one of three enzymes encoded by the HIV genome and is essential for viral replication, and HIV-1 IN inhibitors have emerged as a new promising class of therapeutics. Recently, we reported the synthesis of orally bioavailable azaindole hydroxamic acids that were potent inhibitors of the HIV-1 IN enzyme. Here we disclose the design and synthesis of novel tricyclic N-hydroxy-dihydronaphthyridinones as potent, orally bioavailable HIV-1 integrase inhibitors displaying excellent ligand and lipophilic efficiencies.
MeSH terms
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Administration, Oral
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Animals
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Biological Availability
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Cell Membrane Permeability
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Cells, Cultured
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Dogs
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Drug Design
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HIV Integrase Inhibitors / chemical synthesis*
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HIV Integrase Inhibitors / pharmacokinetics
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HIV Integrase Inhibitors / pharmacology
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HIV-1 / drug effects*
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HIV-1 / enzymology
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Hepatocytes / metabolism
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / pharmacokinetics
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Liver / metabolism
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Molecular Conformation
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Naphthyridines / chemical synthesis*
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Naphthyridines / pharmacokinetics
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Naphthyridines / pharmacology
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Structure-Activity Relationship
Substances
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HIV Integrase Inhibitors
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Heterocyclic Compounds, 3-Ring
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Naphthyridines