生物活性

• 描述Protease-activated receptor 1 (PAR1) is a thrombin-activated receptor that contributes to inflammatory responses at mucosal surfaces^[5]. Vorapaxar is an orally effective thrombin receptor (par-1) antagonist with a Ki value of 8.1 nM in cell-free assay^[6]. The compound showed potent inhibition of thrombin-induced platelet aggregation with an IC50 of 47 nM and haTRAP-induced platelet aggregation with an IC50 of 25 nM, whereas it showed no inhibition of platelet aggregation induced by other agonists such as ADP, collagen, and a PAR-4 agonist peptide^[6]. In additional functional assays, vorapaxar inhibited thrombin-induced calcium transient in human coronary artery smooth muscle cells (HCASMC) with a Ki of 1.1 nM, it also inhibited thrombin-stimulated thymidine incorporation in HCASMC with a Ki of 13 nM^[6]. Pharmacokinetic profiling of vorapaxar was done in rat and monkey models. Following oral administration, vorapaxar was well absorbed in rat (68%; 10 mg/kg) and in monkey (82%; 1 mg/kg) models. T_max was observed at about 3 h in rats and 1 h in monkeys. The elimination half-life was 5.1 h in rats and 13 h in monkeys. The oral bioavailability was 33% in rats and 86% in monkeys^[6]. In an ex vivo cynomolgus monkey model of platelet aggregation, vorapaxar was 30 times more potent than the initial development candidate in the series, showing complete obliteration of agonist induced platelet activation at 0.1 mg/kg with >24 h duration of activity (versus comparable efficacy at 3 mg/kg for the initial candidate) ^[6].

• 动物研究
  剂量	Rat: 10 mg/kg[3] (p.o.); 10 mg/kg[4] (i.v.) Monkey: 1 mg/kg[3] (p.o.)
  给药途径	p.o., i.v.
  动物药代数据	Animal Rats[4] Monkeys[4] Dose 10 mg/kg 1 mg/kg Administration i.v. or p.o. i.v. or p.o. F 33% (p.o.) 86% (p.o.) T1/2 5.1 h (i.v.) 13 h (i.v.) Tmax 3.3 h (p.o.) 1.0 h (p.o.) MRT 3.6 h (i.v.) 5.3 h (p.o.) 13 h (i.v.) 11 h (p.o.) Cmax 0.33 μg/ml (p.o.) 0.65 μg/ml (p.o.) CL 21 ml/min/kg (i.v.) 3.0 ml/min/kg (i.v.) AUC0-48h 7.9 μg·h/ml (i.v.) 2.6 μg·h/ml (p.o.) AUC0→48h 5.6 μg·h/ml (i.v.) 4.8 μg·h/ml (p.o.) Vss 4.6 L/kg (i.v.) 2.2 L/kg (i.v.) Absorption 68% (p.o.) 75% (p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT02660866	Peripheral Arterial Disease	Phase 4	Recruiting	July 2019	United States, Arizona ... more >> Southern Arizona VA Health Care System Recruiting Tucson, Arizona, United States, 85723 Contact: Madhan Shanmugasundaram, MD    520-792-1450 ext 4624    madhan.shanmugasundaram@va.gov    Contact: Sandra Velasquez    520-792-1450 ext 5691    Sandra.Velasquez@va.gov    Principal Investigator: Madhan Shanmugasundaram, MD          United States, California San Diego VA Medical center Recruiting San Diego, California, United States, 92161 Contact: Matthew Allison, MD    858-552-8585 ext 3289    mallison@ucsd.edu    Contact: Amelia Parnell       amelia.parnell@va.gov    Principal Investigator: Matthew Allison, MD          United States, Colorado VA Eastern Colorado Healthcare System Recruiting Denver, Colorado, United States, 80220 Contact: Ehrin Armstrong, MD    916-762-2666    ehrin.armstrong@va.gov    Contact: Caitlin Hutchinson    303-399-8020 ext 4019    Caitlin.hutchinson@va.gov    Principal Investigator: Ehrin Armstrong, MD          United States, Georgia Atlanta Heart Specialists Recruiting Atlanta, Georgia, United States, 30084 Contact: Narendra Singh, MD    678-679-1065    disingh@ahsmed.com    Contact: Kati Raynes       kati@ahsmed.com    Principal Investigator: Narendra Singh, MD          United States, Minnesota Minneapolis Heart Institute Foundation Recruiting Minneapolis, Minnesota, United States, 55407 Contact: Nedaa Skeik, MD    612-863-6800    nedaa.skeik@allina.com    Contact: Laura Onstot    612-863-6120    laura.onstot@allina.com    Principal Investigator: Nedaa Skeik, MD          Minneapolis VA Medical center Recruiting Minneapolis, Minnesota, United States, 55417 Contact: Santiago Garcia, MD    612-467-3670    santiago.garcia@va.gov    Contact: Rebekah Hermann, RN    612-467-3668    rebekah.herrmann@va.gov    Principal Investigator: Santiago Garcia, MD          United States, Nebraska Creighton University Recruiting Omaha, Nebraska, United States, 68131 Contact: Syed Mohiuddin, MD    402-280-4635    smm@creighton.edu    Contact: Brittni Gochnauer    402-280-4448    brittnigochnauer@creighton.edu    Principal Investigator: Syed Mohiuddin, MD          United States, New York Northwell Health Recruiting Manhasset, New York, United States, 11030 Contact: Mitchell Weinberg, MD    516-562-4100    mweinberg@northwell.edu    Contact: Vidya Seeratan    516-562-2653    vseeratan@northwell.edu    Principal Investigator: Mitchell Weinberg, MD          United States, Oklahoma OKlahoma VA Medical Center Recruiting Oklahoma City, Oklahoma, United States, 73104 Contact: Faisal Latif, MD    405-456-3686    faisal.latif@va.gov    Contact: Cheryl Adams, RN    405-456-1775    cheryl.adams@va.gov    Principal Investigator: Faisal Latif, MD          United States, Oregon VA Portland Health Care System Recruiting Portland, Oregon, United States, 97239 Contact: Matthew Koopmann, MD    310-478-3711    matthew.koopmann@va.gov    Contact: Joy Usih    503-220-8262 ext 58388    joy.usih@va.gov    Principal Investigator: Matthew Koopmann, MD          United States, Texas VA North Texas Health Care System Recruiting Dallas, Texas, United States, 75216 Contact: Subhash Banerjee, MD    214-857-1608    subhash.banerjee@utsouthwestern.edu    Contact: Ishita Tejani, BDS, MS, MSPH    214-857-3048    ishita.tejani@va.gov    Principal Investigator: Subhash Banerjee, MD          Texas Tech University Health Science Center Recruiting Lubbock, Texas, United States, 79430 Contact: Mac Ansari, MD    806-743-1501    mac.ansari@ttuhsc.edu    Contact: Ronnie Orozco, MS    806-743-6900    ronnie.orozco@ttuhsc.edu    Principal Investigator: Mac Ansari, MD Collapse <<
  NCT00132912	Arterial Obstructive Diseases ... more >> Coronary Disease Collapse <<	Phase 2	Completed	-	-
  NCT02629367	Coronary Artery Disease	Phase 4	Unknown	March 2017	-

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• 参考文献

• [1] Kehinde O, Kunle R. Vorapaxar: A novel agent to be considered in the secondary prevention of myocardial infarction. J Pharm Bioallied Sci. 2016 Apr-Jun;8(2):98-105.

  [2] Khoufache K, Berri F, et al. PAR1 contributes to influenza A virus pathogenicity in mice. J Clin Invest. 2013 Jan;123(1):206-14.

  [3] Chackalamannil S, Wang Y, et al. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem. 2008 Jun 12;51(11):3061-4.

  [4] Vorapaxar

  [5] Khoufache K, Berri F, Nacken W, Vogel AB, Delenne M, Camerer E, Coughlin SR, Carmeliet P, Lina B, Rimmelzwaan GF, Planz O, Ludwig S, Riteau B. PAR1 contributes to influenza A virus pathogenicity in mice. J Clin Invest. 2013 Jan;123(1):206-14. doi: 10.1172/JCI61667. Epub 2012 Dec 3. PMID: 23202729; PMCID: PMC3533265.

  [6] Chackalamannil S, Wang Y, Greenlee WJ, Hu Z, Xia Y, Ahn HS, Boykow G, Hsieh Y, Palamanda J, Agans-Fantuzzi J, Kurowski S, Graziano M, Chintala M. Discovery of a novel, orally active himbacine-based thrombin receptor antagonist (SCH 530348) with potent antiplatelet activity. J Med Chem. 2008 Jun 12;51(11):3061-4. doi: 10.1021/jm800180e. Epub 2008 May 1. PMID: 18447380.

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