Abstract
Introduction of a 5,6-dihydrouracil functionality in the 5-position of N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide 1 led to a series of highly active HIV-1 integrase inhibitors. These compounds displayed low nanomolar activity in inhibiting both the strand transfer process of HIV-1 integrase and viral replication in cells. Compound 11 is a 150-fold more potent antiviral agent than 1, with a CIC(95) of 40 nM in the presence of human serum. It displays good pharmacokinetics when dosed in rats and dogs.
MeSH terms
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Animals
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Benzyl Compounds / chemistry
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Benzyl Compounds / pharmacokinetics
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Benzyl Compounds / pharmacology*
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Biological Availability
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Crystallography, X-Ray
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HIV Integrase Inhibitors / chemistry
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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 / physiology
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Naphthyridines / chemistry
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Naphthyridines / pharmacokinetics
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Naphthyridines / pharmacology*
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Rats
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Uracil / analogs & derivatives*
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Uracil / chemistry
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Virus Replication / drug effects*
Substances
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8-hydroxy-(1,6)naphthyridine-7-carboxylic acid 4-fluorobenzylamide
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Benzyl Compounds
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HIV Integrase Inhibitors
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Naphthyridines
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dihydrouracil
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Uracil