Abstract
We prepared three discreet cohorts of potent non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) based on the recently reported 3-cyanophenoxypyrazole lead 3. Several of these compounds displayed very promising anti-HIV activity in vitro, safety, pharmacokinetic and pharmaceutical profiles. We describe our analysis and conclusions leading to the selection of alcohol 5 (UK-453,061, lersivirine) for clinical development.
MeSH terms
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Acquired Immunodeficiency Syndrome / drug therapy
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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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Cell Line
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Drug Resistance, Viral
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV Reverse Transcriptase / metabolism
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Humans
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Microsomes, Liver / metabolism
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Nitriles / chemical synthesis
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Nitriles / chemistry*
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Nitriles / pharmacokinetics
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacokinetics
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Rats
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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
Substances
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Anti-HIV Agents
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Nitriles
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Pyrazoles
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Reverse Transcriptase Inhibitors
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UK 453,061
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HIV Reverse Transcriptase