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

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 (IC50=19nM) but also excellent functional antagonist activity (IC50=13nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC50=23nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC50>1μM) and COX-1 and COX-2 enzymes (IC50>10μM).