Abstract
Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
MeSH terms
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Animals
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Binding Sites
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CHO Cells / drug effects
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Calcium / metabolism
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Chemokine CCL2 / antagonists & inhibitors
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Chemokine CCL2 / metabolism
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Cricetinae
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Glycine / analogs & derivatives*
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Glycine / chemical synthesis
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Glycine / chemistry
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Glycine / pharmacology
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Humans
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Inhibitory Concentration 50
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Models, Biological
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Monocytes / drug effects*
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Receptors, CCR2
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Receptors, Chemokine / antagonists & inhibitors*
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Receptors, Chemokine / metabolism
Substances
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CCL2 protein, human
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CCR2 protein, human
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Chemokine CCL2
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Receptors, CCR2
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Receptors, Chemokine
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glycine amide
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Calcium
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Glycine