Abstract
Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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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CCR5 Receptor Antagonists*
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Cell Line, Tumor
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Diketopiperazines / chemical synthesis
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Diketopiperazines / chemistry*
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Diketopiperazines / pharmacokinetics
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Diketopiperazines / pharmacology
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Drug Evaluation, Preclinical
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HIV Core Protein p24 / metabolism
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HIV-1 / metabolism
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Humans
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Microsomes, Liver / metabolism
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Rats
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Receptors, CCR5 / metabolism
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Spiro Compounds / chemical synthesis
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacology
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Stereoisomerism
Substances
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Anti-HIV Agents
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CCR5 Receptor Antagonists
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Diketopiperazines
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HIV Core Protein p24
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Receptors, CCR5
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Spiro Compounds