title: 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.affiliation: 7TM Pharma, Fremtidsvej 3, DK-2970 Hørsholm, Denmark. ulven@chem.sdu.dk
authors.forename: Trond
authors.initials: T
authors.lastname: Ulven
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Receveur
authors.forename: Marie
authors.initials: M
authors.lastname: Grimstrup
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Rist
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Frimurer
authors.forename: Lars-Ole
authors.initials: LO
authors.lastname: Gerlach
authors.forename: Jesper Mosolff
authors.initials: JM
authors.lastname: Mathiesen
authors.forename: Evi
authors.initials: E
authors.lastname: Kostenis
authors.forename: Lena
authors.initials: L
authors.lastname: Uller
authors.forename: Thomas
authors.initials: T
authors.lastname: Högberg
mesh_terms: D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D018926:Anti-Allergic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy / Q000276:immunology; D001667:Binding, Competitive; D001682:Biological Availability; D004804:Eosinophils / Q000276:immunology; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D010642:Phenoxyacetates; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D018418:Th2 Cells / Q000276:immunology
chemical_list: C516214:4-bromo-2-(1-phenyl-1H-pyrazole-4-carbonyl)phenoxyacetic acid; D000085:Acetates; D018926:Anti-Allergic Agents; D010642:Phenoxyacetates; D011720:Pyrazoles; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C036293:prostaglandin D2 receptor