Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR.

Abstract Synthesis and structure–activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 ( 6m ), showed not only potent binding affinity (IC 50  = 19 nM) but also excellent functional antagonist activity (IC 50  = 13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC 50  = 23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC 50  >1 μM) and COX-1 and COX-2 enzymes (IC 50  >10 μM).