Isoquinoline derivatives as potent CRTH2 antagonists: Design, synthesis and SAR

Abstract

In this study, we describe the synthesis and structure–activity relationship (SAR) of a series of isoquinoline chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2) antagonists. TASP0376377 (15-20), one of the most potent compounds, showed a potent binding affinity (IC50=19nM) in addition to the excellent functional antagonist activity (IC50=13nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC50=23nM) was in good agreement with its potency as a CRTH2 antagonist. In addition, 15-20 exhibited greater selectivity in binding to CRTH2 than to the DP1 prostanoid receptor (IC50 >1μM) or the enzymes COX-1 and COX-2 (IC50 >10μM).