Skip to main content
SpringerLink
Log in

A Pharmacodynamic Study of CN-218, a Novel Antiplatelet and Antithrombotic Agent Primarily Targeting the P2Y12 Receptor

  • Original Article
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Drugs inhibiting the platelet P2Y12 receptor, such as clopidogrel and prasugrel, are potent antithrombotic agents and are widely used in cardiovascular disease. However, the adverse effects of these drugs have limited their clinical use. For example, clopidogrel resistance occurs in approximately one third of patients, while prasugrel increases the risk of major bleeding. Therefore, new generations of such drugs are of clinical interest.

Methods

In this study, the pharmacodynamics of a new P2Y12 antagonist, CN-218, was compared with that of clopidogrel and prasugrel in rats and mice. The differences between CN-218 and clopidogrel include deuteration of the 7-position methyl carboxylate and the introduction of cinnamate in the 2-position of thiophene.

Results

CN-218 had an antiaggregatory efficacy that was at least five times more potent than that of clopidogrel but not as potent as that of prasugrel. It had a significant impact on activated partial thromboplastin time (APTT), whereby the APTT of CN-218-treated rats was approximately 9 s longer than that of the vehicle- or clopidogrel-treated group, while it had no impact on prothrombin time (PT) in rats. CN-218 had a similar potent antithrombotic effect to that of prasugrel and clopidogrel and also reduced the risk of bleeding compared to prasugrel.

Conclusion

CN-218 may be a promising antithrombotic agent, with potent antiplatelet and significant anticoagulant activity, as well as a lower risk of bleeding compared to clopidogrel and prasugrel.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Yeung J, Li W, Holinstat M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev. 2018;70(3):526–48.

    Article  CAS  Google Scholar 

  2. Cattaneo M. The platelet P2Y(1)(2) receptor for adenosine diphosphate: congenital and drug-induced defects. Blood. 2011;117(7):2102–12.

    Article  CAS  Google Scholar 

  3. Born GV. Adenosine diphosphate as a mediator of platelet aggregation in vivo: an editorial view. Circulation. 1985;72(4):741–6.

    Article  CAS  Google Scholar 

  4. Murugappa S, Kunapuli SP. The role of ADP receptors in platelet function. Front Biosci. 2006;11:1977–86.

  5. Yeung J, Holinstat M. Newer agents in antiplatelet therapy: a review. J blood med. 2012;3:33–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation. 1999;100(15):1667–72.

    Article  CAS  Google Scholar 

  7. Miao J, Liu R, Li Z. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(21):2250–1.

    CAS  PubMed  Google Scholar 

  8. Gremmel T, Panzer S. Clinical, genetic and confounding factors determine the dynamics of the in vitro response/non response to clopidogrel. Thromb Haemost. 2011;106(2):211–8.

    CAS  PubMed  Google Scholar 

  9. Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal. 2012;8(3):609–19.

    Article  CAS  Google Scholar 

  10. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045–57.

    Article  CAS  Google Scholar 

  11. Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, et al. Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361(24):2330–41.

    Article  CAS  Google Scholar 

  12. Shan J, Zhang B, Zhu Y, Jiao B, Zheng W, Qi X, et al. Overcoming clopidogrel resistance: discovery of vicagrel as a highly potent and orally bioavailable antiplatelet agent. J Med Chem. 2012;55(7):3342–52.

    Article  CAS  Google Scholar 

  13. Lu N, Li L, Zheng X, Zhang S, Li Y, Yuan J et al. Synthesis of a Novel Series of Amino Acid Prodrugs Based on Thienopyridine Scaffolds and Evaluation of Their Antiplatelet Activity. Molecules (Basel, Switzerland). 2018;23(5).

  14. Margaret Bradbury EH, Marantz Y, Baillie T, Stamler D. Site-specific deuterium substitution: A viable approach in drug discovery and development. Drug Met Pharmacokinet. 2018;34(1, Supplement):S8–9.

    Article  Google Scholar 

  15. Xu X, Zhao X, Yang Z, Wang H, Meng X, Su C et al. Significant Improvement of Metabolic Characteristics and Bioactivities of Clopidogrel and Analogs by Selective Deuteration. Molecules (Basel, Switzerland). 2016;21(6).

  16. Xu Z, Gu J, Gao M, Du N, Liu P, Xu X, et al. Study on antiplatelet effect of a new thiophenopyridine platelets P2Y12 receptor antagonist DV-127. Thromb Res. 2018;170:192–9.

    Article  CAS  Google Scholar 

  17. Pontiki E, Peperidou A, Fotopoulos I, Hadjipavlou-Litina D. Cinnamate hybrids: a unique family of compounds with multiple biological activities. Curr Pharm Biotechnol. 2018;19(13):1019–48.

    Article  CAS  Google Scholar 

  18. Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962;194:927–9.

    Article  CAS  Google Scholar 

  19. Bekemeier H, Hirschelmann R, Giessler AJ. Carrageenin-induced thrombosis in rats and mice: a model for testing antithrombotic substances? Agents actions. 1985;16(5):446–51.

    Article  CAS  Google Scholar 

  20. Sanderson K. Big interest in heavy drugs. Nature. 2009;458(7236):269.

    CAS  PubMed  Google Scholar 

  21. Hagihara K, Kazui M, Ikenaga H, Nanba T, Fusegawa K, Takahashi M, et al. Comparison of formation of thiolactones and active metabolites of prasugrel and clopidogrel in rats and dogs. Xenobiotica. 2009;39(3):218–26.

  22. Qiu Z, Li N, Wang X, Tian F, Liu Q, Song L, et al. Pharmacokinetics of vicagrel, a promising analog of clopidogrel, in rats and beagle dogs. J Pharm Sci. 2013;102(2):741–9.

    Article  CAS  Google Scholar 

  23. Sugidachi A, Asai F, Ogawa T, Inoue T, Koike H. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129(7):1439–46.

    Article  CAS  Google Scholar 

  24. Sugidachi A, Ogawa T, Kurihara A, Hagihara K, Jakubowski JA, Hashimoto M, et al. The greater in vivo antiplatelet effects of prasugrel as compared to clopidogrel reflect more efficient generation of its active metabolite with similar antiplatelet activity to that of clopidogrel's active metabolite. J Thromb Haemost. 2007;5(7):1545–51.

    Article  CAS  Google Scholar 

  25. Wang KH, Li SF, Zhao Y, Li HX, Zhang LW. In Vitro Anticoagulant Activity and Active Components of Safflower Injection. Molecules (Basel, Switzerland). 2018;23(1).

  26. Arrieta-Baez D, Dorantes-Alvarez L, Martinez-Torres R, Zepeda-Vallejo G, Jaramillo-Flores ME, Ortiz-Moreno A, et al. Effect of thermal sterilization on ferulic, coumaric and cinnamic acids: dimerization and antioxidant activity. J Sci Food Agric. 2012;92(13):2715–20.

    Article  CAS  Google Scholar 

  27. Hadjipavlou-Litina D, Pontiki E. Aryl-acetic and cinnamic acids as lipoxygenase inhibitors with antioxidant, anti-inflammatory, and anticancer activity. Methods mol biology (Clifton, NJ). 2015;1208:361–77.

  28. Guzman JD. Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity. Molecules (Basel, Switzerland). 2014;19(12):19292–349.

  29. Lapeyre C, Delomenede M, Bedos-Belval F, Duran H, Negre-Salvayre A, Baltas M. Design, synthesis, and evaluation of pharmacological properties of cinnamic derivatives as antiatherogenic agents. J Med Chem. 2005;48(26):8115–24.

    Article  CAS  Google Scholar 

  30. Kurup A, Kumar AV, Rao MN. Anti-inflammatory activity of cinnamic acids. Die Pharmazie. 1989;44(12):870.

    CAS  PubMed  Google Scholar 

  31. Song F, Li H, Sun J, Wang S. Protective effects of cinnamic acid and cinnamic aldehyde on isoproterenol-induced acute myocardial ischemia in rats. J Ethnopharmacol. 2013;150(1):125–30.

    Article  CAS  Google Scholar 

  32. Hagimori M, Kamiya S, Yamaguchi Y, Arakawa M. Improving frequency of thrombosis by altering blood flow in the carrageenan-induced rat tail thrombosis model. Pharmacol Res. 2009;60(4):320–3.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Conn Hastings, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

This work was supported by the Health and Family Planning Commission of Jilin Province (No. 2017 J055) and the Education Department of Jilin Province (No. JJKH20190009KJ).

Author information

Authors and Affiliations

  1. Department of Pharmacology, School of Pharmacy, Jilin University, Fujin Road, Changchun, Jilin, 130021, China

    Xiaohua Li, Peng Liu, Zhiping Xu, Yujia Miao, Jujin Zhang & Xia Cao

  2. Department of Infectious Diseases, The first hospital of Jilin University, Changchun, Jilin, 130021, China

    Xiaohua Li

  3. College of Life Sciences, Jilin University, Qianjin Street, Changchun, Jilin, 130012, China

    Dong Sun & Jingkai Gu

  4. Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, School of Pharmacy, Yantai University, Yantai, 264005, China

    Dong Sun

Authors
  1. Xiaohua Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiping Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dong Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jingkai Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yujia Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jujin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Xia Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization of study, Xia Cao and Jinkai Gu; experimental design, Xiaohua Li, Peng Liu, and Zhiping Xu; performed the experiments, Xiaohua Li, Peng Liu, Zhiping Xu, Dong Sun, Yujia Miao, and Jujin Zhang; data analysis and interpretation, Xiaohua Li, Peng Liu, and Xia Cao; funding acquisition and supervision, Xia Cao; original manuscript draft preparation, Xiaohua Li; reviewing and editing the manuscript, Xiaohua Li. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Xia Cao.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

This study was approved by the Animal Experiment Committee of Jilin University. Experimental mice and rats were housed with 12/12 h dark/light cycles and standard food and water under specific sterile (SPF) conditions. All mice and rats were provided with anesthesia and postoperative care.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Liu, P., Xu, Z. et al. A Pharmacodynamic Study of CN-218, a Novel Antiplatelet and Antithrombotic Agent Primarily Targeting the P2Y12 Receptor. Cardiovasc Drugs Ther 34, 15–23 (2020). https://doi.org/10.1007/s10557-019-06930-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-019-06930-9

Keywords

Search

Navigation