Abstract
Hits from an in silico derived focused library for CRTH2 were transformed into highly selective antagonists with favorable ADME properties. Oral administration of 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid (19) inhibited peribronchial eosinophilia and mucus cell hyperplasia in a mouse model of allergic asthma, supporting the therapeutic potential of this novel compound class. In addition, this selective pharmacological tool compound provides further evidence for CRTH2 as a relevant therapeutic target for treatment of Th2- and eosinophil-related inflammation.
MeSH terms
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Acetates / chemical synthesis
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Acetates / chemistry*
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Acetates / pharmacology
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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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Asthma / drug therapy
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Asthma / immunology
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Binding, Competitive
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Biological Availability
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Eosinophils / immunology
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Fluorescence Resonance Energy Transfer
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Humans
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In Vitro Techniques
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Inflammation / drug therapy
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Inflammation / immunology
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Mice
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Models, Molecular
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Phenoxyacetates
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Pyrazoles / chemical synthesis
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Pyrazoles / chemistry*
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Pyrazoles / pharmacology
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Radioligand Assay
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Rats
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Receptors, Immunologic / antagonists & inhibitors*
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Receptors, Prostaglandin / antagonists & inhibitors*
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Stereoisomerism
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Structure-Activity Relationship
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Th2 Cells / immunology
Substances
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4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid
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Acetates
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Anti-Allergic Agents
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Phenoxyacetates
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Pyrazoles
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Receptors, Immunologic
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Receptors, Prostaglandin
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prostaglandin D2 receptor