New azole antagonists with high affinity for the P2Y1 receptor

Demystifying P2Y1 Receptor Ligand Recognition through Docking and Molecular Dynamics Analyses

“…14–23 BPTU is a non-nucleotide antagonist ( K i = 6.0 nM) belonging to a series of arylurea derivatives that require a hydrophobic character for P2Y 1 R affinity, which has also been explored for antithrombotic activity. 24–30…”

“…Molecular recognition at the P2Y 1 R has been studied using site-directed mutagenesis (SDM) 9,31,37–41 (Table 1), and SAR analysis of both nucleotide 14–23 and non-nucleotide 24–30,34–36 ligands (mainly antagonists). Unlike for other Class A GPCRs, the lack of a suitable receptor template severely limited the success of structure-based approaches, which relied upon homology models to elucidate the ligand recognition at the P2YRs.…”

“…From a pharmacological perspective, MRS2500 is a high affinity ( K i = 0.8 nM) P2Y 1 R-selective antagonist that was shown to inhibit ADP-induced platelet aggregation and thrombus formation in rodents and the cynomolgus monkey. , From the structural standpoint, MRS2500 is a nucleoside 3′,5′-bisphosphate containing a sterically constrained bicyclo­[3.1.0]­hexane (methanocarba) ring system in a North (N) conformation in place of the ribose tetrahydrofuryl ring . Nucleotide-like ligands are well-known P2Y 1 Rs binders, and in the last two decades extensive synthetic efforts have been devoted to elucidating their SAR. − BPTU is a non-nucleotide antagonist ( K i = 6.0 nM) belonging to a series of arylurea derivatives that require a hydrophobic character for P2Y 1 R affinity, which has also been explored for antithrombotic activity. − …”

“…Molecular recognition at the P2Y 1 R has been studied using site-directed mutagenesis (SDM) ,,− (Table ), and SAR analysis of both nucleotide − and non-nucleotide − ,− ligands (mainly antagonists). Unlike for other Class A GPCRs, the lack of a suitable receptor template severely limited the success of structure-based approaches, which relied upon homology models to elucidate the ligand recognition at the P2YRs. , The availability of P2YR crystallographic structures ,, now offers the opportunity to decipher at the molecular level the SAR and SDM data at the P2Y 1 R by analyzing ligand–receptor interaction patterns with high resolution.…”

Drug-like Antagonists of P2Y Receptors—From Lead Identification to Drug Development

“…In order to address the poor physicochemical properties of their lead compounds, scientists at BMS looked into bioisostere replacements of the core urea moiety. In a series of papers they explored replacement of the urea with 2-amino-1,3,4-thiadiazole and 2-amino-1,3-thiazole mimetics ( 16 and 17 , respectively; Figure ). High P2Y 1 R antagonism was demonstrated for a range of azole bioisosteric replacements (e.g., 16 ).…”