Inhibition of the thrombin-platelet reactions by DuP 714

Biochem Biophys Res Commun. 1991 Sep 30;179(3):1500-8. doi: 10.1016/0006-291x(91)91742-u.

Abstract

The efficacy and specificity of a novel synthetic thrombin inhibitor, DuP 714, on thrombin-induced elevation of cytoplasmic calcium, fibrinogen binding and aggregation in human platelets were examined. Thrombin (0.5 U/ml) stimulated an increase in [125I]fibrinogen binding in gel-filtered platelets which was blocked by DuP 714 with an IC50 value of 2 nM. Thrombin (1 U/ml)-induced elevation of intracellular [Ca2+]i was also blocked by DuP 714 with an IC50 value of 67 nM. A much higher concentration of thrombin (25 U/ml) was used to stimulate aggregation with heparinized platelet-rich plasma. Under these conditions, micromolar concentrations of DuP 714 were needed to inhibit thrombin. In all of these preparations, DuP 714 at concentrations as high as 10(-5) M had no intrinsic effects and did not affect the responses induced by arachidonate, ADP, collagen, epinephrine, vasopressin and serotonin. These data indicate that DuP 714 is a potent and specific thrombin inhibitor capable of arresting the actions of thrombin on human fibrin formation and platelet aggregation and secretion. It may serve as a potential antithrombotic agent for various forms of thrombotic disorders.

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Arachidonic Acid / pharmacology
  • Blood Platelets / drug effects
  • Blood Platelets / physiology*
  • Boron Compounds / pharmacology*
  • Collagen / pharmacology
  • Epinephrine / pharmacology
  • Fibrinogen / metabolism
  • Hirudins / pharmacology
  • Humans
  • Kinetics
  • Oligopeptides / pharmacology*
  • Platelet Aggregation / drug effects*
  • Platelet Membrane Glycoproteins / metabolism*
  • Thrombin / antagonists & inhibitors
  • Thrombin / pharmacology*

Substances

  • Boron Compounds
  • Hirudins
  • Oligopeptides
  • Platelet Membrane Glycoproteins
  • acetylphenylalanyl-prolyl-boroarginine
  • Arachidonic Acid
  • Adenosine Diphosphate
  • Fibrinogen
  • Collagen
  • Thrombin
  • Epinephrine