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

J Med Chem. 2006 Nov 16;49(23):6638-41. doi: 10.1021/jm060657g.

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

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

Substances

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