Abstract

Prostaglandin D2 (PGD2) is a potent prostanoid released from mast cells in response to allergens. Chemoattractant receptorhomologous molecule expressed on Th2 cells (CRTh2, also known as DP2), a G-protein coupled receptor for PGD2 and related metabolites, mediates chemotaxis/activation of basophils, eosinophils and Th2 lymphocytes along with production of IL-4, IL-5 and IL-13 from this subset of lymphocytes. Selective antagonism of CRTh2 offers a therapeutic approach for the treatment of allergic disease and, accordingly, drug discovery efforts were initiated. A set of substituted phenyl acetic acids were prepared and evaluated for binding affinity to the CRTh2 receptor. Selectivity over related prostanoid receptors was also evaluated. In the event, compound 2x (2-(4-(4-(4- chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)acetic acid) was identified as a potent, selective, functionally active CRTh2 antagonist. Moreover, compound 2x demonstrated good plasma exposure in rodents upon oral dosing and provided protection from inflammation in a murine model of delayed-type hypersensitivity.