Abstract
HIV type-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) are key drugs of highly active antiretroviral therapy (HAART) in the clinical management of AIDS/HIV infection. NNRTI-based HAART regimes effectively suppress viral reproduction, are not cytotoxic and show favourable pharmacokinetic properties. First-generation NNRTIs suffer the rapid selection of viral variants, hampering the binding of inhibitors into the reverse transcriptase (RT) non-nucleoside binding site (NNBS). Efforts to improve these first inhibitors led to the discovery of second-generation NNRTIs that proved to be effective against the drug-resistant mutant HIV-1 strains. The success of such agents launched a new season of NNRTI design and synthesis. This paper reviews the characteristics of second-generation NNRTIs, including etravirine, rilpivirine, RDEA-806, UK-453061, BIRL 355 BS, IDX 899, MK-4965 and HBY 097. In particular, the binding modes of these inhibitors into the NNBS of the HIV-1 RT and the most clinically relevant mutant RTs are analysed and discussed.
MeSH terms
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / metabolism
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Anti-HIV Agents / pharmacology*
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Antiretroviral Therapy, Highly Active
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Binding Sites
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Cell Line
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Drug Design
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Drug Resistance, Viral
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HIV Infections / drug therapy*
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HIV Infections / virology
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / genetics
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HIV Reverse Transcriptase / metabolism
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HIV-1 / drug effects*
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Humans
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Indoles / chemistry
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Indoles / metabolism
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Indoles / pharmacology
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Models, Molecular
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Molecular Conformation
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Nitriles / chemistry
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Nitriles / pharmacology
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Phosphinic Acids / chemistry
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Phosphinic Acids / metabolism
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Phosphinic Acids / pharmacology
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Pyrazoles / chemistry
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Pyrazoles / pharmacology
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Pyridazines / chemistry
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Pyridazines / pharmacology
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Pyridines / chemistry
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Pyridines / pharmacology
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Quinoxalines / chemistry
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Quinoxalines / pharmacology
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Reverse Transcriptase Inhibitors / chemistry*
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Reverse Transcriptase Inhibitors / metabolism
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Reverse Transcriptase Inhibitors / pharmacology*
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Rilpivirine
Substances
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3-(5-((6-amino-1H-pyrazolo(3,4-b)pyridine-3-yl)methoxy)-2-chlorophenoxy)-5-chlorobenzonitrile
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Anti-HIV Agents
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IDX 899
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Indoles
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Nitriles
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Phosphinic Acids
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Pyrazoles
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Pyridazines
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Pyridines
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Pyrimidines
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Quinoxalines
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Reverse Transcriptase Inhibitors
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UK 453,061
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etravirine
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reverse transcriptase, Human immunodeficiency virus 1
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HIV Reverse Transcriptase
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Rilpivirine
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HBY 097