ACS Publications. Most Trusted. Most Cited. Most Read
My Activity

Fibrinolysis Inhibitors: Potential Drugs for the Treatment and Prevention of Bleeding

Cite this: J. Med. Chem. 2020, 63, 4, 1445–1472
Publication Date (Web):October 28, 2019
Copyright © 2019 American Chemical Society

    Article Views





    Other access options


    Abstract Image

    Hyperfibrinolytic situations can lead to life-threatening bleeding, especially during cardiac surgery. The approved antifibrinolytic agents such as tranexamic acid, ε-aminocaproic acid, 4-aminomethylbenzoic acid, and aprotinin were developed in the 1960s without the structural insight of their respective targets. Crystal structures of the main antifibrinolytic targets, the lysine binding sites on plasminogen’s kringle domains, and plasmin’s serine protease domain greatly contributed to the structure-based drug design of novel inhibitor classes. Two series of ligands targeting the lysine binding sites have been recently described, which are more potent than the most-widely used antifibrinolytic agent, tranexamic acid. Furthermore, four types of promising active site inhibitors of plasmin have been developed: tranexamic acid conjugates targeting the S1 pocket and primed sites, substrate-analogue linear homopiperidylalanine-containing 4-amidinobenzylamide derivatives, macrocyclic inhibitors addressing nonprimed binding regions, and bicyclic 14-mer SFTI-1 analogues blocking both, primed and nonprimed binding sites of plasmin. Furthermore, several allosteric plasmin inhibitors based on heparin mimetics have been developed.

    Read this article

    To access this article, please review the available access options below.

    Get instant access

    Purchase Access

    Read this article for 48 hours. Check out below using your ACS ID or as a guest.


    Access through Your Institution

    You may have access to this article through your institution.

    Your institution does not have access to this content. You can change your affiliated institution below.

    Cited By

    This article is cited by 19 publications.

    1. Ponnusamy Pon Sathieshkumar, Metlapalli Durga Anand Saibabu, Rajagopal Nagarajan. A Cascade Approach for the Synthesis of 5-(Indol-3-yl)hydantoin: An Application to the Total Synthesis of (±)-Oxoaplysinopsin B. The Journal of Organic Chemistry 2021, 86 (5) , 3730-3740.
    2. Marvin Korff, Lukas Imberg, Jonas M. Will, Nico Bückreiß, Svetlana A. Kalinina, Benjamin M. Wenzel, Gregor A. Kastner, Constantin G. Daniliuc, Maximilian Barth, Ruzanna A. Ovsepyan, Kirill R. Butov, Hans-Ulrich Humpf, Matthias Lehr, Mikhail A. Panteleev, Antti Poso, Uwe Karst, Torsten Steinmetzer, Gerd Bendas, Dmitrii V. Kalinin. Acylated 1H-1,2,4-Triazol-5-amines Targeting Human Coagulation Factor XIIa and Thrombin: Conventional and Microscale Synthesis, Anticoagulant Properties, and Mechanism of Action. Journal of Medicinal Chemistry 2020, 63 (21) , 13159-13186.
    3. Om Darlami, Rabin Pun, Sung-Hoon Ahn, Seok-Ho Kim, Dongyun Shin. Macrocyclization strategy for improving candidate profiles in medicinal chemistry. European Journal of Medicinal Chemistry 2024, 272 , 116501.
    4. Tojofaniry Fabien Rakotondrabe, Minxia Fan, Guangwan Hu, Mingquan Guo. Potential hemostatic compounds targeting urokinase plasminogen activator explored from three Euphorbiaceae species: Euphorbia maculata , Euphorbia humifusa , and Acalypha australis , with bio‐affinity ultrafiltration UPLC‐MS. Phytochemical Analysis 2024, 35 (1) , 28-39.
    5. François Marceau. Drugs of the Kallikrein–Kinin System: An Overview. Drugs and Drug Candidates 2023, 2 (3) , 538-553.
    6. Simon J. A. Wiedemeyer, Guojie Wu, T. L. Phuong Pham, Heike Lang‐Henkel, Benjamin Perez Urzua, James C Whisstock, Ruby H. P. Law, Torsten Steinmetzer. Synthesis and Structural Characterization of Macrocyclic Plasmin Inhibitors. ChemMedChem 2023, 18 (6)
    7. Joanna Kolodziejczyk-Czepas, Jan Czepas. Plant-Derived Compounds and Extracts as Modulators of Plasmin Activity—A Review. Molecules 2023, 28 (4) , 1677.
    8. Anne-Sophie Bouthors, Sixtine Gilliot, Loïc Sentilhes, Benjamin Hennart, Emmanuelle Jeanpierre, Catherine Deneux-Tharaux, Gilles Lebuffe, Pascal Odou. The role of tranexamic acid in the management of postpartum haemorrhage. Best Practice & Research Clinical Anaesthesiology 2022, 36 (3-4) , 411-426.
    9. Lingyan Zhang, Yingting Wu, Xingling Luo, Tianjiang Jia, Kexin Li, Lihong Zhou, Zhen Mao, Peili Huang. A novel insight into mechanism of derangement of coagulation balance: interactions of quantum dots with coagulation-related proteins. Particle and Fibre Toxicology 2022, 19 (1)
    10. Oriol Bosch-Sanz, Yvette Rabadà, Xevi Biarnés, Javier Pedreño, Luis Caveda, Mercedes Balcells, Jordi Martorell, David Sánchez-García. 1,2,3-Triazole Derivatives as Novel Antifibrinolytic Drugs. International Journal of Molecular Sciences 2022, 23 (23) , 14942.
    11. Calvin Dunker, Lukas Imberg, Alena I. Siutkina, Catharina Erbacher, Constantin G. Daniliuc, Uwe Karst, Dmitrii V. Kalinin. Pyrazole-Based Thrombin Inhibitors with a Serine-Trapping Mechanism of Action: Synthesis and Biological Activity. Pharmaceuticals 2022, 15 (11) , 1340.
    12. Fanny Risser, Ivan Urosev, Joanan López-Morales, Yang Sun, Michael A. Nash. Engineered Molecular Therapeutics Targeting Fibrin and the Coagulation System: a Biophysical Perspective. Biophysical Reviews 2022, 14 (2) , 427-461.
    13. Il-Sup Kim, Cher-Won Hwang, Woong-Suk Yang, Cheorl-Ho Kim. Current Perspectives on the Physiological Activities of Fermented Soybean-Derived Cheonggukjang. International Journal of Molecular Sciences 2021, 22 (11) , 5746.
    14. Dino Mehic, Ingrid Pabinger, Cihan Ay, Johanna Gebhart. Fibrinolysis and bleeding of unknown cause. Research and Practice in Thrombosis and Haemostasis 2021, 5 (4) , e12511.
    15. Yuko Tsuda, Koushi Hidaka, Keiko Hojo, Yoshio Okada. Exploration of Active Site-Directed Plasmin Inhibitors: Beyond Tranexamic Acid. Processes 2021, 9 (2) , 329.
    16. Brian A. Bruckner, William D. Spotnitz, Erik Suarez, Matthias Loebe, Uy Ngo, Daniel L. Gillen, Roberto J. Manson. Evaluation of the Safety and Efficacy of a Novel Thrombin Containing Combination Hemostatic Powder Using a Historical Control. Clinical and Applied Thrombosis/Hemostasis 2021, 27 , 107602962110172.
    17. Milena M. Awad, Melanie L. Hutton, Adam J. Quek, William P. Klare, Steven J. Mileto, Kate Mackin, Diane Ly, Viola Oorschot, Marijana Bosnjak, Grant Jenkin, Paul J. Conroy, Nick West, Alex Fulcher, Adam Costin, Christopher J. Day, Michael P. Jennings, Robert L. Medcalf, Martina Sanderson-Smith, Stuart J. Cordwell, Ruby H.P. Law, James C. Whisstock, Dena Lyras. Human Plasminogen Exacerbates Clostridioides difficile Enteric Disease and Alters the Spore Surface. Gastroenterology 2020, 159 (4) , 1431-1443.e6.
    18. Sven Ullrich, Christoph Nitsche. The SARS-CoV-2 main protease as drug target. Bioorganic & Medicinal Chemistry Letters 2020, 30 (17) , 127377.
    19. Dorothea Bestle, Miriam Ruth Heindl, Hannah Limburg, Thuy Van Lam van, Oliver Pilgram, Hong Moulton, David A Stein, Kornelia Hardes, Markus Eickmann, Olga Dolnik, Cornelius Rohde, Hans-Dieter Klenk, Wolfgang Garten, Torsten Steinmetzer, Eva Böttcher-Friebertshäuser. TMPRSS2 and furin are both essential for proteolytic activation of SARS-CoV-2 in human airway cells. Life Science Alliance 2020, 3 (9) , e202000786.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    Pair your accounts.

    Export articles to Mendeley

    Get article recommendations from ACS based on references in your Mendeley library.

    You’ve supercharged your research process with ACS and Mendeley!

    STEP 1:
    Click to create an ACS ID

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Please note: If you switch to a different device, you may be asked to login again with only your ACS ID.

    Your Mendeley pairing has expired. Please reconnect