Abstract
Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K(i) = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.
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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Drug Evaluation, Preclinical
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HIV-1 / drug effects
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Humans
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In Vitro Techniques
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Leukocytes, Mononuclear / virology
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Macaca fascicularis
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Oximes
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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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Piperidines*
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Rats
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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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Cyclic N-Oxides
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Oximes
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Piperazines
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Piperidines
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Pyridines
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Ancriviroc