Abstract
Our laboratory has identified several acrylamide derivatives with potent CCR3 inhibitory activity. In the present study, we evaluated the in vitro metabolic stability (CL(int); mL/min/kg) of these compounds in human liver microsomes (HLMs), and assessed the relationship between their structures and CL(int) values. Among the compounds identified, N-{(3R)-1-[(6-fluoro-2-naphthyl)methyl]pyrrolidin-3-yl}-2-[1-(2-hydroxybenzoyl)piperidin-4-ylidene]acetamide (30j) was found to be a potent inhibitor (IC(50)=8.4nM) with a high metabolic stability against HLMs.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / chemistry
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Acetamides / pharmacology
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Acrylamides / chemical synthesis
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Acrylamides / chemistry*
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Acrylamides / pharmacokinetics
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Animals
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Anti-Allergic Agents / chemical synthesis*
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Anti-Allergic Agents / chemistry
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Anti-Allergic Agents / pharmacokinetics
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Haplorhini
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Humans
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Mice
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Microsomes, Liver / metabolism
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Naphthalenes / chemical synthesis*
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Naphthalenes / chemistry
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Naphthalenes / pharmacology
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Piperidines / chemical synthesis
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Piperidines / chemistry
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Piperidines / pharmacology
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / metabolism
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Receptors, CCR3 / antagonists & inhibitors*
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Receptors, CCR3 / metabolism
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Thermodynamics
Substances
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Acetamides
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Acrylamides
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Anti-Allergic Agents
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N-((3R)-1-((6-fluoro-2-naphthyl)methyl)pyrrolidin-3-yl)-2-(1-(2-hydroxybenzoyl)piperidin-4-ylidene)acetamide
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Naphthalenes
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Piperidines
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Protein Isoforms
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Receptors, CCR3