Pharmacological Characterization of TASP0412098, A Selective CRTH2 (Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells) Antagonist

Chemoattractant receptor-homologous molecule expressed on Th2 (CRTH2) is a G protein-coupled receptor (GPCR) which expresses on Th2 cells, eosinophils and basophils. Prostaglandin D2 (PGD2), an arachidonic acid metabolite produced by mast cells, acts as the ligand of CRTH2. It has been suggested that the interaction between CRTH2 and PGD2 might have important role(s) in allergic diseases such as bronchial asthma, allergic rhinitis and atopic dermatitis. We succeeded in optimization of a novel CRTH2 antagonist, the isoquinoline derivative TASP0412098, and examined biological activities and pharmacological efficacies on allergic responses. Receptor binding assay was performed by CRTH2 transfected cells. Antagonistic activity was determined by intracellular Ca2+ influx using CRTH2 transfected cells, migration assay and IL-13 production assay performed by Th2 cells derived from healthy adult volunteer. Eosinophil shape change assay was performed by eosinophil derived from peripheral blood cells of guinea pig. In vivo efficacy were examined using guinea pig asthma model and murine contact allergic dermatitis model. TASP0412098 exhibited strong inhibitory effects on CRTH2-PGD2 interaction (IC50: 2.1nM) in highly specific manner.In cellular studies, TSAP0412098 also inhibited PGD2-induced intracellular Ca2+ influx, Th2 cells migration and IL-13 production from Th2 cells. Administration of TASP0412098 attenuated eosinophil shape change reaction at ex vivo, suppressed bronchial asthmatic responses in guinea pigs and inflammatory responses in contact allergic dermatitis model in mice. CRTH2 plays important roles in allergic diseases, and TASP0412098 is a useful compound for the treatment of allergic diseases.