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 (IC 50  = 19 nM) in addition to the excellent functional antagonist activity (IC 50  = 13 nM). Moreover, the efficacy of this compound in a chemotaxis assay (IC 50  = 23 nM) 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 (IC 50 >1 μM) or the enzymes COX-1 and COX-2 (IC 50 >10 μM).