Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects

Protease-activated receptor 1 knockout reduces experimentally induced liver fibrosis

“…This is especially appealing, since contrary to direct thrombin inhibitors, PAR-1 antagonists do not provoke a bleeding risk, and there is moreover great hope that orally active molecules will be available (reviewed in Ref. 6). Finally, the fact that deletion of a single PAR-1 allele was enough to offer a very significant protection suggests that complete blockage of PAR-1 function may not be required for a therapeutic effect.…”

“…We evaluated the mRNA levels of collagen ␣ 1 (I), a major component of liver fibrosis, PDGF-␤ receptor, a marker of fibrogenic cell activation, and MMP-2, implicated in extracellular matrix remodeling, using real-time quantitative RT-PCR. The median collagen ␣ 1 (I)-to-/RLP0 ratio was 2.25 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) in the control group, whereas it reached 59.5 (18.80 -233.20) in PAR-1 ϩ/ϩ mice treated for 6 wk with CCl 4 . As shown in Fig.…”

Overview of the 2014 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee Meeting About Vorapaxar

“…In preclinical studies, vorapaxar demonstrated a >100-fold selectivity to PAR-1 over a panel of >100 receptors, ion channels, and enzymes. 10,11,14,15 Vorapaxar is a first-in-class antiplatelet drug of the PAR-1 antagonist family that inhibits thrombin-related platelet aggregation by a mechanism distinct from aspirin and P2Y 12 receptor inhibitors. It does not affect ADP-mediated platelet aggregation, coagulation parameters, or bleeding time.…”

“…The study drug, vorapaxar (Zontivity, Merck, NJ), is an antagonist of the platelet protease-activated receptor (PAR-1) and inhibits thrombin-induced platelet aggregation. 10,11 Vorapaxar was shown to have a significant benefit for the reduction of cardiovascular death and ischemic complications in addition to secondary prevention. 12 Vorapaxar was also tested in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial as part of adjunct therapy in the non-ST-segment-elevation ACS population.…”

Unchecked thrombin is bad news for troubled arteries

“…As DS does not activate AT, DS therapy might correct a defect specific to the atheroma and thus provide local anticoagulation without perturbing normal hemostasis. An alternative strategy to target this pathway may be through PARs (3,5,21). As human platelets carry PAR4 as a low-affinity "backup" receptor for thrombin, PAR1 antagonism might limit thrombosis and most cellular actions of thrombin while retaining fibrin formation and enough residual platelet activation to prevent bleeding.…”