Abstract
A series of N1-heterocyclic pyrimidinediones were extensively evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Inhibitor 1 is active against NNRTI-resistant viruses including RT mutant K103N. The co-crystal structure of inhibitor 1 with HIV-1 RT revealed that H-bonds are formed with K101 and K103. Efforts to improve the suboptimal pharmacokinetic profile of 1 resulted in the discovery of compound 13, which represents the lead compound in this series with improved pharmacokinetics and similar potency as inhibitor 1.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis
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Anti-HIV Agents / chemistry*
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Anti-HIV Agents / pharmacokinetics
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Binding Sites
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Crystallography, X-Ray
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Dogs
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / metabolism
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Heterocyclic Compounds / chemistry*
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Humans
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Hydrogen Bonding
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Microsomes / metabolism
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Mutant Proteins / antagonists & inhibitors
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Mutant Proteins / metabolism
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Pyrimidinones / chemical synthesis
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Pyrimidinones / chemistry*
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Pyrimidinones / pharmacokinetics
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Reverse Transcriptase Inhibitors / chemical synthesis
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Reverse Transcriptase Inhibitors / chemistry*
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Reverse Transcriptase Inhibitors / pharmacokinetics
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Structure-Activity Relationship
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Thymine / analogs & derivatives*
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Thymine / chemical synthesis
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Thymine / chemistry
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Thymine / pharmacokinetics
Substances
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Anti-HIV Agents
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Heterocyclic Compounds
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Mutant Proteins
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Pyrimidinones
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Reverse Transcriptase Inhibitors
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase
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Thymine