AR-C118925

The P2Y₂ receptor (P2Y₂R) is a target for diseases including cancer, idiopathic pulmonary fibrosis, and atherosclerosis. However, there are insufficient P2Y₂R antagonists available for validating P2Y₂R function and future drug development. Evaluation of how (R)-5-(7-chloro-2-((2-ethoxyethyl)amino)-4H-benzo[5,6]cyclohepta[1,2-d]thiazol-4-yl)-1-methyl-4-thioxo-3,4-dihydropyrimidin-2(1H)-one, a previously published thiazole-based analogue of AR-C118925, binds in a P2Y₂R homology model was used to design new P2Y₂R antagonist scaffolds. One P2Y₂R antagonist scaffold retained millimolar affinity for the P2Y₂R and upon further functionalization with terminal carboxylic acid groups affinity was improved over 100-fold. This functionalized P2Y₂R antagonist scaffold was employed to develop new chemotype P2Y₂R fluorescent ligands, that were attainable in a convergent five-step synthesis. One of these fluorescent ligands demonstrated micromolar affinity (pK _d = 6.02 ± 0.12, n = 5) for the P2Y₂R in isolated cell membranes and distinct pharmacology from an existing P2Y₂R fluorescent antagonist, suggesting it may occupy a different binding site on the P2Y₂R.

P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14). The widely expressed P2Y receptors play important roles in physiology and pathophysiology. This review summarizes the use of pharmacological tools to characterize the P2Y receptor subtypes involved in these responses. MRS2500 is a potent and selective antagonist acting at the P2Y1 receptor. AR-C118925 is useful for the selective antagonism of the P2Y2 receptor. PSB16133 blocks the P2Y4 receptor, MRS2578 is an antagonist at the P2Y6 receptor and NF157 as well as NF340 block the P2Y11 receptor. ADP-induced platelet aggregation is mediated by P2Y1 and P2Y12 receptors. A number of compounds or their active metabolites reduce ADP-induced platelet aggregation by blocking the P2Y12 receptor. These include the active metabolites of the thienopyridine compounds clopidogrel and prasugrel, the nucleoside analogue ticagrelor and the nucleotide analogue cangrelor. PSB0739 is also a potent antagonist at the P2Y12 receptor useful for both in vitro and in vivo studies. MRS2211 and MRS2603 inhibit P2Y13 mediated responses. PPTN is a very potent antagonist at the P2Y14 receptor.