Functionalized Congeners of 2 H -Chromene P2Y 6 Receptor Antagonists.

The P2Y 6 receptor (P2Y 6 R), a G q -coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2 H -chromene derivatives, although high affinity is lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced affinity in the antagonism of UDP-induced Ca 2+ mobilization in human (h) P2Y 6 R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino- n -heptylethynyl) analogue 30 (MRS4940) had an IC 50 of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative 30 , and 132-fold selective compared to the P2Y 14 R. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2Y 6 R affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives 20 , 24 , 26 , 30 , 31 , and 37 , which showed multiple interactions, particularly at the biogenic amine receptors. The more potent analogues may be suitable for evaluation in inflammation and cancer models, which will be performed in future studies.