# Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists

## TL;DR

Researchers developed new compounds that strongly block the P2Y6 receptor, which could be useful for treating inflammation and degenerative diseases.

## Contribution

The study introduces amino-functionalized congeners with significantly enhanced P2Y6 receptor antagonism compared to prior compounds.

## Key findings

- A 6-(Boc-amino-n-heptylethynyl) analogue (MRS4940) showed 162 nM IC50 in human P2Y6R cells.
- Affinity was 123-fold higher than the corresponding primary alkylamine and 107-fold higher than the pivaloyl derivative.
- The P2Y6R affinity was influenced by chain length, attachment point, and terminal functionality.

## Abstract

The P2Y6 receptor (P2Y6R), a Gq-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)-2H-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 Ca2+ mobilization in human (h) P2Y6R-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino-n-heptylethynyl) analogue 30 (MRS4940) had an IC50 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 P2Y14R. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2Y6R 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.