Switching a Xanthine Oxidase Inhibitor to a Dual-Target Antagonist of P2Y1 and P2Y12 as an Oral Antiplatelet Agent with a Wider Therapeutic Window in Rats than Ticagrelor

J Med Chem. 2020 Dec 24;63(24):15752-15772. doi: 10.1021/acs.jmedchem.0c01524. Epub 2020 Dec 12.

Abstract

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.

MeSH terms

  • Animals
  • Binding Sites
  • Cytochrome P-450 Enzyme System / chemistry
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Stability
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology
  • Half-Life
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / metabolism
  • Imidazoles / pharmacology
  • Mice
  • Microsomes, Liver / metabolism
  • Molecular Docking Simulation
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemistry*
  • Platelet Aggregation Inhibitors / metabolism
  • Platelet Aggregation Inhibitors / pharmacology
  • Purinergic P2Y Receptor Antagonists / chemistry*
  • Purinergic P2Y Receptor Antagonists / metabolism
  • Rats
  • Receptors, Purinergic P2Y1 / chemistry*
  • Receptors, Purinergic P2Y1 / metabolism
  • Receptors, Purinergic P2Y12 / chemistry*
  • Receptors, Purinergic P2Y12 / metabolism
  • Structure-Activity Relationship
  • Ticagrelor / pharmacology
  • Xanthine Oxidase / antagonists & inhibitors*
  • Xanthine Oxidase / metabolism

Substances

  • Enzyme Inhibitors
  • Imidazoles
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Receptors, Purinergic P2Y1
  • Receptors, Purinergic P2Y12
  • imidazole
  • Cytochrome P-450 Enzyme System
  • Xanthine Oxidase
  • Ticagrelor