Functionalized Congeners of 2-Chromene P2Y Receptor Antagonists.

The P2Y receptor (P2YR), a G-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-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 mobilization in (h) P2YR-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino--heptylethynyl) analogue (MRS4940) had an IC of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative , and 132-fold selective compared to the P2YR. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2YR affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives , , , , , and , 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.