Discovery of a New Class of Potent, Selective, and Orally Bioavailable CRTH2 (DP2) Receptor Antagonists for the Treatment of Allergic Inflammatory Diseases

A novel chemical class of potent chemoattractant receptor-homologous expressed on Th2 lymphocytes (CRTH2 or DP2) antagonists is reported. An initial and moderately potent spiro-indolinone compound (5) was found during a high-throughput screening campaign. Structure−activity relationship (SAR) investigation around the carboxylic acid group revealed that changes in this part of the molecule could lead to a reversal of functional activity, yielding weakly potent agonists. SAR investigation of the succinimide functional group led to the discovery of several single-digit nanomolar antagonists. The potency of these compounds was confirmed in a human eosinophil chemotaxis assay. Moreover, compounds (R)-58 and (R)-71 were shown to possess pharmacokinetic properties suitable for development as an orally bioavailable drug.