Share This Article:

Recent Development in Thrombin Receptor Antagonist as Novel Antithrombotic Agent

Full-Text HTML Download Download as PDF (Size:503KB) PP. 112-118
DOI: 10.4236/ojmc.2012.24014    3,493 Downloads   7,243 Views   Citations

ABSTRACT

Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.

Cite this paper

H. Cui, W. Tan, J. Shi and Y. Xia, "Recent Development in Thrombin Receptor Antagonist as Novel Antithrombotic Agent," Open Journal of Medicinal Chemistry, Vol. 2 No. 4, 2012, pp. 112-118. doi: 10.4236/ojmc.2012.24014.

References

[1] L. D. J. Angiolillo, D. Capodanno and S. Goto, “Platelet Thrombin Receptor Antagonism and Atherothrombosis,” European Heart Journal, Vol. 31, No. 1, 2010, pp. 17-28. Hdoi:10.1093/eurheartj/ehp504
[2] S. R. Coughlin, “Protease-Activated Receptors in Hemostasis, Thrombosis and Vascular Biology,” Journal of Thrombosis and Haemostasis, Vol. 3, No. 8, 2005, pp. 18001814. Hdoi:10.1111/j.1538-7836.2005.01377.x
[3] G. Bisacchi, “Anticoagulants, Antithrombotics, and Hemostatics,” In: D. J. Abraham, Ed., Burger’s Medicinal Chemistry and Drug Discovery, 6th Edition, John Wiley and Sons, Inc., Hoboken, 2003, pp. 283-338. Hdoi:10.1002/0471266949
[4] T. K. Vu, D. T. Hung, V. I. Wheaton and S. R. Coughlin, “Molecular Cloning of a Functional Thrombin Receptor Reveals a Novel Proteolytic Mechanism of Receptor Activation,” Cell, Vol. 64, No. 6, 1991, pp. 1057-1068. Hdoi:10.1016/0092-8674(91)90261-V
[5] S. Chackalamannil, “Thrombin Receptor (Protease Activated Receptor-1) Antagonists as Potent Antithrombotic Agents with Strong Antiplatelet Effects,” Journal of Medicinal Chemistry, Vol. 49, No. 18, 2006, pp. 5389-5403. Hdoi:10.1021/jm0603670
[6] S. Chackalamannil and Y. Xia, “Thrombin Receptor (PAR1) Antagonists as Novel Antithrombotic Agents,” Expert Opinion on Therapeutic Patents, Vol. 16, No. 4, 2006, pp. 493-505.
[7] S. Chackalamannil, Y. Wang, W. J. Greenlee, Z. Hu, Y. Xia, H. S. Ahn, et al. “Discovery of a Novel, Orally Active Himbacine-Based Thrombin Receptor Antagonist (SCH 530348) with Potent Antiplatelet Activity,” Journal of Medicinal Chemistry, Vol. 51, No. 11, 2008, pp. 30613064. Hdoi:10.1021/jm800180e
[8] T. Kosoglou, L. Reyderman, R. Tiessen, R. R. Fales, D. L. Cutler, R. Keller, et al. “TRAP-Induced Platelet Aggregation Following Single and Multiple Rising Doses of SCH 530348, a Novel Thrombin Receptor Antagonist, in Healthy Volunteers (Abstract),” Clinical Pharmacology & Therapeutics, Vol. 85, No. Supplement 1, 2009, p. S21.
[9] Y. Abdulsattar, T. Ternas and D. Garcia, “Vorapaxar: Targeting a Novel Antiplatelet Pathway,” Pharmacy and Therapeutics, Vol. 36, No. 9, 2011, pp. 564-568.
[10] R. C. Becker, D. J. Moliterno, L. K. Jennings, et al. “Safety and Tolerability of SCH530348 in Patients Undergoing Non-Urgent Percutaneous Coronary Intervention: A Randomised, Double-Blind, Placebo Controlled Phase II study,” Lancet, Vol. 373, No. 9667, 2009, pp. 919-928. Hdoi:10.1016/S0140-6736(09)60230-0
[11] S. Goto, T. Yamaguchi, Y. Ikeda, et al. “Safety and Exploratory Efficacy of the Novel Thrombin Receptor (PAR1) Antagonist SCH530348 for Non-ST-Segment Elevation Acute Coronary Syndrome,” Journal of Atherosclerosis & Thrombosis, Vol. 17, No. 2, 2010, pp. 156-164. Hdoi:10.5551/jat.3038
[12] P. Tricoci, Z. Huang, C. Held, D. J. Moliterno, P. W. Armstrong, F. V. de Werf, et al., for the TRACER Investigators, “Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes,” The New England Journal of Medicine, Vol. 366, No. 1, 2012, pp. 20-33. Hdoi:10.1056/NEJMoa1109719
[13] D. A. Morrow, E. Braunwald, M. P. Bonaca, S. F. Ameriso, A. J. Dalby, M. P. Fish, et al., for the TRA 2P-TIMI 50 Steering Committee and Investigators, “Vorapaxar in the Secondary Prevention of Atherothrombotic Events,” The New England Journal of Medicine, Vol. 366, No. 15, 2012, pp. 1404-1413. Hdoi:10.1056/NEJMoa1200933
[14] B. M. Scirica, M. P. Bonaca, E. Braunwald, G. M. De Ferrari, D. Isaza, B. S. Lewis, et al., for the TRA 2°PTIMI 50 Steering Committee Investigators, “Vorapaxar for Secondary Prevention of Thrombotic Events for Patients with Previous Myocardial Infarction: A Prespecified Subgroup Analysis of the TRA 2°P-TIMI 50 trial,” Lancet, Vol. 380, No. 9850, 2012, pp. 1317-1324. Hdoi:10.1016/S0140-6736(12)61269-0
[15] M. P. Bonaca, D. A. Morrow and E. Braunwald, “Vorapaxar for Secondary Prevention in Patients with Peripheral Artery Disease: Results from the Peripheral Artery Disease Cohort of the TRA 2°P-TIMI 50 Trial,” Circulation, Vol. 126, No. 4, 2012, pp. 520-521. Hdoi:10.1161/CIR.0b013e3182611cc2
[16] M. Kogushi, T. Matsuoka, T. Kawata, H. Kuramochi, S. Kawaguchi, K. Murakami, et al., “The Novel and Orally Active Thrombin Receptor Antagonist E5555 (Atopaxar) Inhibits Arterial Thrombosis without Affecting Bleeding Time in Guinea Pigs,” European Journal of Pharmacology, Vol. 657, No. 1, 2011, pp. 131-137. Hdoi:10.1016/j.ejphar.2011.01.058
[17] M. L. O’Donoghue, D. L. Bhatt, S. D. Wiviott, S. G. Goodman, D. J. Fitzgerald, D. J. Angiolillo, S. Goto, et al., LANCELOT-ACS Investigators, “Safety and Tolerability of Atopaxar in the Treatment of Patients with Acute Coronary Syndromes: The Lessons from Antagonizing the Cellular Effects of Thrombin-Acute Coronary Syndromes Trial,” Circulation, Vol. 123, No. 17, 2011, pp. 18431853. Hdoi:10.1161/CIRCULATIONAHA.110.000786
[18] S. Goto, H. Ogawa, M. Takeuchi, M. D. Flather and D. L. Bhatt, on Behalf of the J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators, “Double-Blind, Placebo-Controlled Phase II Studies of the Protease-Activated 1 Antagonist E5555 (Atopaxar) in Japanese Patients with Acute Coronary Syndrome or High-Risk Coronary Disease,” European Heart Journal, Vol. 31, No. 21, 2010, pp. 2601-2613. Hdoi:10.1093/eurheartj/ehq320
[19] V. L. Serebruany, M. Kogushi, D. Dastros-Pitei, M. Flather and D. L. Bhatt, “The In-Vitro Effects of E5555, a Protease-Activated Receptor (PAR)-1 Antagonist, on Platelet Biomarkers in Healthy Volunteers and Patients with Coronary Artery Disease,” Journal of Thrombosis and Haemostasis, Vol. 102, No. 1, 2009, pp. 111-119.
[20] H. Lu, P. C. Tang, Y. Chen, S. Wang, H. Wang, L. Zhang and J. Li, “5,5-Disubstituted-2-imino-pyrrolidine Derivatives, Preparation Methods and Pharmaceutical Uses Thereof,” Patent Cooperation Treaty International Application, 2011, Publication No. WO/2011/ 140936.
[21] D. Heimbach, S. Roehrig, Y. Cancho Grande, D. Schneider, U. Rester, E. Bender, et al., “Substituted 3-(1,2,4-Oxadiazol-3-yl)-5-phenylpiperidines as PAR-1 Antagonists and Their Preparation and Use in the Treatment of Cardiovascular and Tumor Diseases.” Patent Cooperation Treaty International Application, 2010, Publication No. WO 2010/136127.
[22] M. Perez, M. Lamothe, C. Maraval, E. Mirabel, C. Loubat, B. Planty, et al. “Discovery of Novel Protease Activated Receptors 1 Antagonists with Potent Antithrombotic Activity in Vivo,” Journal of Medicinal Chemistry, Vol. 52, No. 19, 2009, pp. 5826-5836. Hdoi:10.1021/jm900553j
[23] R. Létienne, A. Leparq-Panissié, Y. Calmettes, F. NadalWollbold, M. Perez and B. Le Grand, “Antithrombotic Activity of F 16618, a New PAR1 Antagonist Evaluated in Extracorporeal Arterio-Venous Shunt in the Rat,” Biochemical Pharmacology, Vol. 79, No. 11, 2010, pp. 16161621. Hdoi:10.1016/j.bcp.2010.02.006
[24] M. Dumas, F. Nadal-Wollbold, P. Gaussem, M. Perez, T. Mirault, R. Letienne, et al., “Antiplatelet and Antithrombotic Effect of F 16618, a New Thrombin Proteinase-Activated Receptor-1 (PAR1) Antagonist,” British Journal of Pharmacology, Vol. 165, No. 6, 2012, pp. 1827-1835. Hdoi:10.1111/j.1476-5381.2011.01668.x
[25] P. Chieng-Yane, A. Bocquet, R. Létienne, T. Bourbon, S. Sablayrolles, M. Perez, et al., “Protease-Activated Receptor-1 Antagonist F 16618 Reduces Arterial Restenosis by Down-Regulation of Tumor Necrosis Factor ? and Matrix Metalloproteinase 7 Expression, Migration, and Proliferation of Vascular Smooth Muscle Cells,” Journal of Pharmacology and Experimental Therapeutics, Vol. 336, No. 3, 2011, pp. 643-651. Hdoi:10.1124/jpet.110.175182
[26] C. Dockendorff, O. Aisiku, L. VerPlank, J. R. Dilks, D. A. Smith, S. F. Gunnink, et al., “Discovery of 1,3-Diaminobenzenes as Selective Inhibitors of Platelet Activation at the PAR1 Receptor,” ACS Medicinal Chemistry Letters, Vol. 3, No. 3, 2012, pp. 232-237. Hdoi:10.1021/ml2002696

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.