Vorapaxar: a novel protease-activated receptor-1 inhibitor.

Abstract

INTRODUCTION:

Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences.

AREAS COVERED:

Only 20% relative risk (∼ 2% absolute risk) reduction associated with newer P2Y(12) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombin-protease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations - vorapaxar and atopaxar. In preclinical and Phase I - II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns.

EXPERT OPINION:

At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor.

• Authors: Paul A Gurbel, Young-Hoon Jeong, Udaya S Tantry
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 20 Issue 10 Pg. 1445-53 (Oct 2011) ISSN: 1744-7658 [Electronic] England
• PMID: 21819272 (Publication Type: Journal Article, Review)

Chemical References

• Lactones
• Platelet Aggregation Inhibitors
• Pyridines
• Receptor, PAR-1
• vorapaxar

Topics

• Clinical Trials as Topic
• Female
• Humans
• Lactones (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Male
• Molecular Targeted Therapy
• Platelet Aggregation Inhibitors (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Pyridines (adverse effects, pharmacokinetics, pharmacology, therapeutic use)
• Receptor, PAR-1 (antagonists & inhibitors)