Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits.

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.

• Authors: Trond Ulven, Jean-Marie Receveur, Marie Grimstrup, Øystein Rist, Thomas M Frimurer, Lars-Ole Gerlach, Jesper Mosolff Mathiesen, Evi Kostenis, Lena Uller, Thomas Högberg
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 23 Pg. 6638-41 (Nov 16 2006) ISSN: 0022-2623 [Print] United States
• PMID: 17154491 (Publication Type: Journal Article)

Chemical References

• 4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid
• Acetates
• Anti-Allergic Agents
• Phenoxyacetates
• Pyrazoles
• Receptors, Immunologic
• Receptors, Prostaglandin
• prostaglandin D2 receptor

Topics

• Acetates (chemical synthesis, chemistry, pharmacology)
• Animals
• Anti-Allergic Agents (chemical synthesis, chemistry, pharmacology)
• Asthma (drug therapy, immunology)
• Binding, Competitive
• Biological Availability
• Eosinophils (immunology)
• Fluorescence Resonance Energy Transfer
• Humans
• In Vitro Techniques
• Inflammation (drug therapy, immunology)
• Mice
• Models, Molecular
• Phenoxyacetates
• Pyrazoles (chemical synthesis, chemistry, pharmacology)
• Radioligand Assay
• Rats
• Receptors, Immunologic (antagonists & inhibitors)
• Receptors, Prostaglandin (antagonists & inhibitors)
• Stereoisomerism
• Structure-Activity Relationship
• Th2 Cells (immunology)