Abstract
Based on the original spirodiketopiperazine design framework, further optimization of an orally available CCR5 antagonist was undertaken. Structural hybridization of the hydroxylated analog 4 derived from one of the oxidative metabolites and the new orally available non-hydroxylated benzoic acid analog 5 resulted in another potent orally available CCR5 antagonist 6a as a clinical candidate. Full details of a structure-activity relationship (SAR) study and ADME properties are presented.
Copyright © 2011 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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Benzoates / chemical synthesis
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Benzoates / chemistry*
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Benzoates / pharmacokinetics
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CCR5 Receptor Antagonists*
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Diketopiperazines / chemical synthesis
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Diketopiperazines / chemistry*
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Diketopiperazines / pharmacokinetics
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Dogs
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Drug Evaluation, Preclinical
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Guinea Pigs
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Haplorhini
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Humans
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Rabbits
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Rats
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Receptors, CCR5 / metabolism
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Structure-Activity Relationship
Substances
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4-(4-((1-butyl-3-(cyclohexyl(hydroxy)methyl)-2,5-dioxo-1,4,9-triazaspiro(5.5)undec-9-yl)methyl)phenoxy)benzoic acid
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Anti-HIV Agents
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Benzoates
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CCR5 Receptor Antagonists
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Diketopiperazines
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Receptors, CCR5