Protease-activated receptor-1 inhibitors: a novel class of antiplatelet agents for the treatment of patients with acute coronary syndrome.
The unifying basis of acute coronary syndrome (ACS) is the complication of a vulnerable coronary plaque, an event primarily mediated by platelet activation. Three major pathways are predominantly involved in this process: thromboxane A(2) via the thromboxane A(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1, with the latter being the most potent platelet activator. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, respectively, the recurrence of ischemic events in patients with ACS remains high. There is also a growing concern regarding the safety profile in terms of bleeding with more powerful antiplatelet agents, which has tempered expectations of newly developed compounds. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preliminary data indicate that these compounds have the potential to improve ischemic prognosis without increasing the bleeding risk. In this chapter we will discuss the rationale for developing this novel class of antiplatelet agents and specifically, the two compounds in most advanced clinical development, vorapaxar and atopaxar.
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Sergio
S
Leonardi
Pierluigi
P
Tricoci
Richard C
RC
Becker
D054058:Acute Coronary Syndrome / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D000818:Animals; D006801:Humans; D007097:Imines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007783:Lactones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017202:Myocardial Ischemia / Q000150:complications; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D018179:Receptors, Thrombin / Q000187:drug effects / Q000502:physiology; D010975:Platelet Aggregation Inhibitors
C540445:E 5555; D007097:Imines; D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors