Abstract
Replacement of the 5-oxopyrrolidin-3-yl fragment in the previously reported lead structure with a 1-acetylpiperidin-4-yl group led to the discovery of a novel series of potent CCR5 antagonists. Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists. The selected compound 11f showed excellent antiviral activity against CCR5-using HIV-1 replication in human peripheral blood mononuclear cells (EC50=0.59 nM) and an acceptable pharmacokinetic profile in dogs.
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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Anti-HIV Agents / pharmacology
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CCR5 Receptor Antagonists*
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CHO Cells
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COS Cells
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Chlorocebus aethiops
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Cricetinae
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Cricetulus
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Dogs
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HIV-1 / drug effects
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Humans
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Male
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Rats
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Receptors, CCR5 / chemistry
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Structure-Activity Relationship
Substances
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Anti-HIV Agents
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CCR5 Receptor Antagonists
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Piperidines
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Receptors, CCR5