Abstract
New phenoxyacetic acid antagonists of CRTH2 are described. Following the discovery of a hit compound by a focused screening, high protein binding was identified as its main weakness. Optimization aimed at reducing serum protein binding led to the identification of several compounds that showed not only excellent affinities for the receptor (41 compounds with K(i) < 10 nM) but also excellent potencies in a human whole blood assay (IC(50) < 100 nM; PGD2-induced eosinophil shape change). Additional optimization of the PK characteristics led to the identification of several compounds suitable for in vivo testing. Of these, 19k and 19s were tested in two different pharmacological models (acute FITC-mediated contact hypersensitivity and ovalbumin-induced eosinophilia models) and found to be active after oral dosing (10 and 30 mg/kg).
MeSH terms
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Acetates / chemical synthesis*
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Acetates / pharmacokinetics
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Acetates / pharmacology
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Administration, Oral
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Alkynes / chemical synthesis*
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Alkynes / pharmacokinetics
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Alkynes / pharmacology
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Animals
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Anti-Allergic Agents / chemical synthesis*
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Anti-Allergic Agents / pharmacokinetics
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Anti-Allergic Agents / pharmacology
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / pharmacokinetics
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Anti-Inflammatory Agents / pharmacology
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Binding, Competitive
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Blood Proteins / metabolism
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Caco-2 Cells
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Cell Membrane Permeability
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Cell Shape
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Chemotaxis, Leukocyte
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Dermatitis, Contact / drug therapy
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Eosinophils / drug effects
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Eosinophils / pathology
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Eosinophils / physiology
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Female
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HEK293 Cells
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Humans
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Mice
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Mice, Inbred BALB C
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Microsomes, Liver / metabolism
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Ovalbumin / immunology
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Phenoxyacetates
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Protein Binding
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Pulmonary Eosinophilia / drug therapy
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Pulmonary Eosinophilia / immunology
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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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Structure-Activity Relationship
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Sulfones / chemical synthesis*
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Sulfones / pharmacokinetics
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Sulfones / pharmacology
Substances
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(4-chloro-2-((2-fluoro-5-(propylsulfonyl)phenyl)ethynyl)phenoxy)acetic acid
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(4-chloro-2-((2-methyl-5-(propylsulfonyl)phenyl)ethynyl)phenoxy)acetic acid
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Acetates
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Alkynes
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Anti-Allergic Agents
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Anti-Inflammatory Agents
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Blood Proteins
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Phenoxyacetates
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Receptors, Immunologic
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Receptors, Prostaglandin
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Sulfones
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Ovalbumin
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prostaglandin D2 receptor