Discovery of potent orally active thrombin receptor (protease activated receptor 1) antagonists as novel antithrombotic agents

J Med Chem. 2005 Sep 22;48(19):5884-7. doi: 10.1021/jm0502236.

Abstract

Structurally novel thrombin receptor (protease activated receptor 1, PAR-1) antagonists based on the natural product himbacine are described. The prototypical PAR-1 antagonist 55 showed a Ki of 2.7 nM in the binding assay, making it the most potent PAR-1 antagonist reported. 55 was highly active in several functional assays, showed excellent oral bioavailability in rat and monkey models, and showed complete inhibition of agonist-induced ex vivo platelet aggregation in cynomolgus monkeys after oral administration.

MeSH terms

  • Administration, Oral
  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Alkaloids / pharmacology
  • Animals
  • Biological Availability
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Chromatography, High Pressure Liquid
  • Fibrinolytic Agents / chemical synthesis*
  • Fibrinolytic Agents / chemistry
  • Fibrinolytic Agents / pharmacology
  • Furans / chemical synthesis*
  • Furans / chemistry
  • Furans / pharmacology
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / chemistry
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • In Vitro Techniques
  • Macaca fascicularis
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Platelet Aggregation Inhibitors / chemical synthesis
  • Platelet Aggregation Inhibitors / chemistry
  • Platelet Aggregation Inhibitors / pharmacology
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptor, PAR-1 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 4-(5-(3-trifluoromethylphenyl)pyridin-2-yl)ethenyl-3-methyldecahydronaphtho(2,3-c)furan-1(3H)-one
  • Alkaloids
  • Fibrinolytic Agents
  • Furans
  • Heterocyclic Compounds, 3-Ring
  • Naphthalenes
  • Piperidines
  • Platelet Aggregation Inhibitors
  • Pyridines
  • Receptor, PAR-1
  • himbacine