Vorapaxar
Vorapaxar 
(previously known as SCH 530348; Merck,Sharp & Dome, USA)
is structurally similar to the natural product himbacine, but completely lacks the muscarinic M2 antagonist activity characteristic of himbacine.
This agent is an orally-active, potent, reversible, and selective inhibitor of the PAR-1 receptor with a very long terminal half-life, which ranges from 126 to 269 h. Although reversible, vorapaxar dissociates very slowly from the PAR-1 receptor, which is a critical requirement to compete effectively with the resident tethered ligand.
Vorapaxar is a direct acting drug (thus not a pro-drug) and is inactivated mainly via the CYP3A4 enzymatic system. Vorapaxar has no significant renal metabolism.
Phase II of Vorapaxar: the TRA-PCI and the Japanese study
The key phase II study with vorapaxar was the TRA-PCI, a large phase II study that tested the safety, tolerability, and preliminary efficacy of this agent in 1,030 patients with stable coronary artery disease (CAD) presumed to be managed with PCI. The study showed similar bleeding incidence as measured by the TIMI scale (major or minor) between placebo and the 3 doses tested of vorapaxar (0.5, 1, and 2.5 mg). Also, exploratory analysis on efficacy showed a numerical reduction in the rate of myocardial infarction, mainly related to PCI. A similarly designed study was conducted in Japan in patients with NSTEACS invasively managed. This additional phase II study in Japanese patients had similar results compared with TRA-PCI. Specifically, this study showed similar incidence of bleeding between placebo and vorapaxar and a reduction of MIs with vorapaxar.
External Links
- Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, Ziada KM, Berman G, Strony J, Joseph D, Mahaffey KW, Van de Werf F, Veltri E, Harrington RA; TRA-PCI Investigators (2009). "Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study". Lancet. 373 (9667): 919–28. PMID 19286091.
- Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. (2010). "Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome". J Atheroscler Thromb. 17 (2): 156–64. PMID 20124733.