PAR-1 ( Ki = 8.1 nM )
SCH 530348 is an orally administered thrombin-receptor antagonist based on himbacine and a synthetic tricyclic 3-phenylpyridine. SCH 530348 exhibits no inhibition of platelet aggregation induced by other agonists such as ADP, collagen, and a PAR-4 agonist peptide, but it exhibits strong inhibition of thrombin-induced platelet aggregation (IC50 of 47 nM) and haTRAP-induced platelet aggregation (IC50 of 25 nM). Additionally, prothrombin time (PT), partial thromboplastin time (PTT), and activated partial thromboplastin time (aPTT) are unaffected by SCH 530348. Furthermore, when SCH 530348 is used in place of an inactive control, there is no increase in bleeding time or surgical bleeding. When SCH530348 is tested against several ion channels and receptors, including the PAR-4 receptor, it is discovered to be selective for PAR-1.[1]

SCH 530348 is an orally administered thrombin-receptor antagonist based on himbacine and a synthetic tricyclic 3-phenylpyridine. SCH 530348 exhibits no inhibition of platelet aggregation induced by other agonists such as ADP, collagen, and a PAR-4 agonist peptide, but it exhibits strong inhibition of thrombin-induced platelet aggregation (IC50 of 47 nM) and haTRAP-induced platelet aggregation (IC50 of 25 nM). Additionally, prothrombin time (PT), partial thromboplastin time (PTT), and activated partial thromboplastin time (aPTT) are unaffected by SCH 530348. Furthermore, when SCH 530348 is used in place of an inactive control, there is no increase in bleeding time or surgical bleeding. When SCH530348 is tested against several ion channels and receptors, including the PAR-4 receptor, it is discovered to be selective for PAR-1.[1]

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Vorapaxar (SCH 530348) binds competitively to human platelet PAR-1 with high affinity (Ki = 8.1 nM). [1]
Vorapaxar potently inhibits thrombin-induced platelet aggregation in human platelet-rich plasma (PRP) with an IC50 of 47 nM and inhibits aggregation induced by the PAR-1 agonist peptide haTRAP with an IC50 of 25 nM. [1]
Vorapaxar shows no inhibition of platelet aggregation induced by other agonists including ADP, collagen, a thromboxane mimetic (U46619), or a PAR-4 agonist peptide, demonstrating selectivity for the PAR-1 pathway. [1]
Vorapaxar inhibits thrombin-stimulated calcium transient in human coronary artery smooth muscle cells (HCASMC) with a Ki of 1.1 nM. [1]
Vorapaxar inhibits thrombin-stimulated thymidine incorporation (a measure of proliferation) in HCASMC with a Ki of 13 nM. [1]
Scatchard plot analysis confirms that Vorapaxar binds to PAR-1 in a competitive manner. [1]
Kinetic studies show that Vorapaxar has a slow dissociation half-life (t1/2) from the PAR-1 receptor of approximately 20 hours. [1]

SCH 530348 is well absorbed in rat (68%; 10 mg/kg) and in monkey (82%; 1 mg/kg) models. In rats, T_max is measured at approximately 3 hours, while in monkeys, it is measured at 1 hour. In rats, the elimination half-life is 5.1 hours, while in monkeys, it is 13 hours. In rats, the oral bioavailability is 33%, while in monkeys, it is 86%. Oral SCH 530348 administration at a dose greater than 0.1 mg/kg resulted in 100% inhibition of thrombin-receptor agonist peptide (TRAP)-induced platelet aggregation for 24 hours, with partial recovery taking place at 48 hours, according to preclinical studies conducted on platelets from cynomolgus monkeys.[1]

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Oral administration of Vorapaxar (0.1 mg/kg and higher) to cynomolgus monkeys produces 100% inhibition of ex vivo haTRAP-induced platelet aggregation for 24 hours, with partial recovery of platelet function observed at 48 hours post-dose. [1]
Vorapaxar is 30 times more potent than an initial candidate in the series, achieving complete inhibition of agonist-induced platelet activation at 0.1 mg/kg compared to 3 mg/kg for the earlier compound. [1]

From 40 units of fresh human platelets, 700 mg of human platelet membranes are made. A thrombin receptor radioligand binding assay modification is used to screen for thrombin receptor antagonists. Human platelet membranes (40μg) are incubated in binding buffer (50 mM Tris-HCl, pH 7.5, 10 mM MgCl₂, 1 mM EGTA, 0.1% BSA) with 10nM of [³H]haTRAP (alanine-p-fluorophenylalaninearganine-cyclohexylalanine-homoarganine-[3H]phenylalanine amide) in the presence of compounds at concentrations of 1 nM, 3 nM, 30 nM, 100 nM, 300 nM, and 1μM (5% DMSO final concentration). The plates are placed on a plate shaker, covered, and gently vortexed for one hour at room temperature. Using a Packard FilterMate Universal Harvester, the incubated membranes are harvested onto Packard UniFilter GF/C filter plates. These plates are soaked in 0.1% polyethyleneimine for at least an hour and then quickly washed four times with 300 μL of ice cold binding buffer without BSA. Each well receives an addition of MicroScint 20 scintillation cocktail, and the plates are counted using a Packard TopCount Microplate Scintillation Counter. In the presence of excess (50 μM) unlabeled haTRAP, the specific binding is defined as the total binding minus the nonspecific binding.

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The in vitro binding affinity of compounds for the PAR-1 receptor was determined using a radioligand binding assay. Human platelet membrane preparations were used as the source of PAR-1. The assay employed a tritium-labeled high-affinity thrombin receptor activating peptide ([3H]haTRAP) as the competing ligand. Test compounds were incubated with the membrane preparation and the radioligand. The concentration of compound required to displace 50% of the specific radioligand binding (Ki) was calculated. [1]

Inhibition of platelet aggregation was assessed using human platelet-rich plasma (PRP). PRP was pre-incubated with Vorapaxar or vehicle before stimulation with various agonists (thrombin, haTRAP, ADP, collagen, etc.). Aggregation was measured, and IC50 values were determined. [1]
Inhibition of calcium mobilization was evaluated in human coronary artery smooth muscle cells (HCASMC). Cells were loaded with a calcium-sensitive fluorescent dye, pre-incubated with Vorapaxar, and then stimulated with thrombin. The resulting increase in intracellular calcium (calcium transient) was measured, and the Ki for inhibition was calculated. [1]
Inhibition of cell proliferation was assessed in HCASMC using a [3H]thymidine incorporation assay. Cells were stimulated with thrombin in the presence or absence of Vorapaxar. Incorporated radioactivity was measured to assess DNA synthesis, and the Ki for inhibition was determined. [1]

cynomolgus monkeys
0.5, 0.3, 0.1, and 0.05 mg/kg
oral

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The ex vivo antiplatelet activity of Vorapaxar was evaluated in cynomolgus monkeys. The compound was administered orally as a suspension in 0.4% methylcellulose vehicle. Blood samples were collected at various time points post-dose. Platelet aggregation in response to haTRAP was measured in whole blood using impedance aggregometry to determine the percentage inhibition over time. [1]
Pharmacokinetic studies were conducted in rats and cynomolgus monkeys. For oral studies, Vorapaxar (as the HCl salt) was administered in 0.4% methylcellulose. For intravenous studies, it was formulated in 20% hydroxypropyl-β-cyclodextrin. Blood samples were collected serially to determine plasma concentration-time profiles. [1]

Absorption, Distribution and Excretion
Vorapaxa is rapidly absorbed after oral administration. Under rapid absorption conditions, the median time to peak plasma concentration (tmax) is 1 hour. Vorapaxa can be taken with or without food, as co-administration with high-fat foods does not significantly alter the AUC. The mean absolute bioavailability is 100%. Vorapaxa is primarily excreted in feces as its metabolite M19 (91.5%), with a partial excretion in urine (8.5%). 424 L

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Metabolism/Metabolites Vorapaxa is metabolized by CYP3A4 and CYP2J2 to the major circulating metabolite M20 and the major fecal metabolite M19.

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Biological Half-Life The effective half-life of vorapax is 3–4 days, and the apparent terminal half-life is 8 days.

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In rats, after oral administration of a 10 mg/kg dose, the oral bioavailability (F) of Vorapaxar was 33%, and the peak plasma concentration (Cmax) was reached at approximately 3 hours (Tmax). The elimination half-life (t1/2) was 5.1 hours. [1]
In cynomolgus monkeys, after oral administration of a 1 mg/kg dose, the oral bioavailability (F) of Vorapaxar was 86%, the time to peak concentration (Tmax) was approximately 1 hour, and the elimination half-life (t1/2) was 13 hours. [1]
Mass balance studies of tritium-labeled Vorapaxar in rats and monkeys showed that the radioactivity was completely recovered within 7 days. [1]

Hepatotoxicity
The incidence of elevated serum enzymes during vorapazal treatment is low, similar to placebo or control therapy. In a large controlled trial involving over 10,000 patients followed for 2 years, the proportion of patients with ALT elevations exceeding 5 times the upper limit of normal was 1% in the vorapazal group, compared to 1.4% in the placebo group. A pooled analysis of laboratory studies from over 39,000 patients treated with vorapazal or placebo revealed that GGT was the only liver function parameter with a higher incidence of abnormalities in the vorapazal group (3.8%) than in the placebo group (3.3%), without reported serious liver-related adverse events or clinically significant liver injury. Therefore, liver injury caused by vorapazal, even if it occurs, is certainly very rare. Probability score: E (unlikely to be the cause of clinically significant liver injury). Protein Binding Vorapazal has a high binding rate (>99%) to human plasma proteins (such as human serum albumin). Vorapaxar does not affect standard coagulation parameters (prothrombin time PT and activated partial thromboplastin time APTT) in vitro, indicating that it does not inhibit the enzymatic activity of thrombin or other prothrombinases. [1] Vorapaxar exhibits selectivity in multiple assays against other G protein-coupled receptors (GPCRs), ion channels, and receptors, and is inactive against PAR-2, PAR-3, and PAR-4. [1] At the tested concentrations, Vorapaxar did not show inhibitory, metabolic inhibitory, or inducing effects on major human cytochrome P450 (CYP450) isoenzymes (CYP1A2, 2C9, 2C19, 2D6, 3A4). [1] Based on its properties, Vorapaxar is considered to have excellent safety and is in full development. [1]

[1]. J Med Chem . 2008 Jun 12;51(11):3061-4.

Vorapaxar is a carbamate, an ethyl ester of [(1R,3aR,4aR,6R,8aR,9S,9aS)-9-{(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethynyl}-1-methyl-3-oxododecanonaphtho[2,3-c]furan-6-yl]carbamate. It is a protease-activated receptor-1 antagonist (used in sulfate form) used to reduce the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease. Studies have shown that it can reduce the incidence of the composite endpoint of cardiovascular death, MI, stroke, and emergency coronary revascularization. It has a dual role as a protease-activated receptor-1 antagonist, platelet aggregation inhibitor, and cardiovascular agent. It belongs to the pyridine, carbamate, organofluorine, naphthofuran, and lactone classes. It is the conjugate base of vorapaxar(1+). Vorapaxa is a tricyclic simbacin derivative and a selective inhibitor of protease-activated receptor 1 (PAR-1), indicated for reducing the incidence of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). Vorapaxa inhibits thrombin-related platelet aggregation by inhibiting PAR-1 expressed on platelets. Vorapaxa is a protease-activated receptor 1 antagonist. Its mechanism of action is as a protease-activated receptor-1 antagonist. Vorapaxa is a platelet aggregation inhibitor used to reduce the risk of recurrent cardiovascular thrombotic events in patients with a history of myocardial infarction or peripheral vascular disease. Vorapaxa treatment is associated with a low incidence of elevated serum transaminases, but has not been associated with clinically significant cases of acute liver injury. Vorapaxa is an orally bioavailable protease-activated receptor-1 (PAR-1) antagonist with antiplatelet activity. After oral administration, vorapaxar binds to PAR-1 expressed on platelets, inhibiting PAR-1-mediated platelet aggregation. Vorapaxar inhibits thrombin-induced and TRAP-induced platelet aggregation, but does not inhibit ADP-, collagen-, or thromboxane analogue-induced platelet aggregation.
See also: Vorapaxar sulfate (active ingredient).
Drug Indications
Vorapaxar is indicated for reducing the risk of thrombotic cardiovascular events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD). It is usually used in combination with acetylsalicylic acid (ASA) and/or clopidogrel, and should therefore be used as adjunctive therapy to these drugs, as it has not been studied alone.
FDA Label
Zontivity is indicated for reducing the risk of atherosclerotic thrombotic events in the following adult patients: those with a history of myocardial infarction (MI), used in combination with acetylsalicylic acid (ASA), and, where appropriate, with clopidogrel; or those with symptomatic peripheral artery disease (PAD), used in combination with acetylsalicylic acid (ASA), or, where appropriate, with clopidogrel.
Prevention of Arterial Thromboembolism

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Mechanism of Action
Vorapaxar inhibits platelet aggregation by reversibly antagonizing protease-activated receptor 1 (PAR-1) (also known as the thrombin receptor). Thrombin receptor (PAR) is a class of G protein-coupled receptors that are highly expressed on platelets and activated by the serine protease activity of thrombin, thereby mediating the thrombotic response. Vorapaxar inhibits thrombin-induced platelet aggregation and thrombin receptor agonist peptide (TRAP)-induced platelet aggregation by blocking PAR-1 activation. Vorapaxar does not inhibit platelet aggregation induced by other agonists such as adenosine diphosphate (ADP), collagen, or thromboxane analogs. Vorapaxar is a fourth-generation, orally administered, active thrombin receptor (PAR-1) antagonist, discovered through optimization of a series of compounds derived from the natural product simbacin. [1] Its mechanism of action involves competitive antagonism of PAR-1, thereby blocking thrombin-mediated platelet activation without interfering with the role of thrombin in fibrinogenesis. This is presumably expected to result in potent antiplatelet activity and a potentially reduced risk of bleeding compared to conventional drugs. [1] As of the time of this publication, Vorapaxar (SCH 530348) is undergoing a Phase III clinical trial for the treatment of acute coronary syndromes (unstable angina/non-ST-segment elevation myocardial infarction) and secondary prevention of cardiovascular events in high-risk patients. [1]

C29H33FN2O4

492.5817

492.242

C, 70.71; H, 6.75; F, 3.86; N, 5.69; O, 12.99

618385-01-6

Vorapaxar sulfate; 705260-08-8

10077130

White to off-white solid powder

1.3±0.1 g/cm3

676.0±55.0 °C at 760 mmHg

362.6±31.5 °C

0.0±2.1 mmHg at 25°C

1.594

4.54

1

6

6

36

821

7

FC1=C([H])C([H])=C([H])C(=C1[H])C1=C([H])N=C(C([H])=C1[H])/C(/[H])=C(\[H])/[C@]1([H])[C@]2([H])[C@@]([H])(C([H])([H])[H])OC([C@]2([H])C([H])([H])[C@]2([H])C([H])([H])[C@@]([H])(C([H])([H])C([H])([H])[C@]21[H])N([H])C(=O)OC([H])([H])C([H])([H])[H])=O

ZBGXUVOIWDMMJE-QHNZEKIYSA-N

InChI=1S/C29H33FN2O4/c1-3-35-29(34)32-23-10-11-24-20(14-23)15-26-27(17(2)36-28(26)33)25(24)12-9-22-8-7-19(16-31-22)18-5-4-6-21(30)13-18/h4-9,12-13,16-17,20,23-27H,3,10-11,14-15H2,1-2H3,(H,32,34)/b12-9+/t17-,20+,23-,24-,25+,26-,27+/m1/s1

ethyl N-[(1R,3aR,4aR,6R,8aR,9S,9aS)-9-[(E)-2-[5-(3-fluorophenyl)pyridin-2-yl]ethenyl]-1-methyl-3-oxo-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-1H-benzo[f][2]benzofuran-6-yl]carbamate

Vorapaxar free base; Vorapaxar; SCH530348; SCH-530348; SCH 530348

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 25~99 mg/mL (50.8~201 mM)
Ethanol: ~99 mg/mL

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (5.08 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 5%DMSO + 40%PEG300 + 5%Tween 80 + 50%ddH2O: 1.67mg/ml (3.39mM)

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 (Please use freshly prepared in vivo formulations for optimal results.)