Novel selective orally active CRTH2 antagonists for allergic inflammation developed from in silico derived hits.
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.
Ulven
Trond
T
7TM Pharma, Fremtidsvej 3, DK-2970 Hørsholm, Denmark. ulven@chem.sdu.dk
Receveur
Jean-Marie
JM
Grimstrup
Marie
M
Rist
Øystein
Ø
Frimurer
Thomas M
TM
Gerlach
Lars-Ole
LO
Mathiesen
Jesper Mosolff
JM
Kostenis
Evi
E
Uller
Lena
L
Högberg
Thomas
T
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
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