Abstract
Structure-activity relationship (SAR) studies of initial screening hits from our corporate library of compounds and a structurally related series of CCR1 receptor antagonists were used to determine that an N-(alkyl)benzylpiperidine is an essential pharmacophore for selective CCR3 antagonists. Further SAR studies that introduced N-(ureidoalkyl) substituents improved the binding potency of these compounds from the micromolar to the low nanomolar range. This new series of compounds also displays highly potent, in vitro functional CCR3-mediated antagonism of eotaxin-induced Ca(2+) mobilization and chemotaxis of human eosinophils.
MeSH terms
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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 / pharmacology
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CHO Cells
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Calcium / metabolism
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Chemokine CCL11
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Chemokines, CC / pharmacology
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Chemotaxis, Leukocyte / drug effects
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Cricetinae
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Eosinophils / cytology
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Eosinophils / drug effects
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Eosinophils / metabolism
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Humans
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In Vitro Techniques
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Receptors, CCR3
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Receptors, Chemokine / antagonists & inhibitors*
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Receptors, Chemokine / metabolism
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Structure-Activity Relationship
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Urea / analogs & derivatives*
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Urea / chemical synthesis*
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Urea / chemistry
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Urea / pharmacology
Substances
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Anti-Allergic Agents
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CCL11 protein, human
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CCR3 protein, human
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Chemokine CCL11
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Chemokines, CC
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Piperidines
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Receptors, CCR3
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Receptors, Chemokine
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Urea
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Calcium