Abstract
Truncation of the original piperidino-2(S)-methyl piperazine lead structure 2, from a family of muscarinic antagonists, gave compound 8 which has improved selectivity for the HIV-1 co-receptor CCR5 over muscarinic receptors. Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs. The title compound (1) has excellent oral bioavailability in rat, dog, and monkey.
MeSH terms
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Administration, Oral
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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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Biological Availability
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CCR5 Receptor Antagonists*
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Cell Line
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Cyclic N-Oxides / chemical synthesis*
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Cyclic N-Oxides / chemistry
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Cyclic N-Oxides / pharmacokinetics
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Cyclic N-Oxides / pharmacology
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Dogs
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HIV-1 / drug effects
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In Vitro Techniques
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Leukocytes, Mononuclear / virology
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Macaca fascicularis
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacokinetics
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Piperazines / pharmacology
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Rats
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Structure-Activity Relationship
Substances
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1-((2,4-dimethyl-3-pyridinyl)carbonyl)-4-methyl-4-(3-methyl-4-(1-(4-(trifluoromethyl)phenyl)ethyl)-1-piperazinyl)piperidine N1-oxide
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Anti-HIV Agents
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CCR5 Receptor Antagonists
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Cyclic N-Oxides
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Piperazines