Development of Thrombin Inhibitors for Cardiovascular Diseases

Thrombin inhibitors are a class of drugs that prevent blood clotting and thrombosis, using in cardiovascular diseases such as atrial fibrillation and myocardial infarction. Ace Therapeutics is advancing cardiovascular drug discovery by offering cutting-edge technical support and research services to facilitate the development of thrombin inhibitors, empowering our clients to achieve breakthrough therapeutic solutions.

The Role of Thrombin in Cardiovascular Diseases

Thrombin is a key enzyme in the coagulation cascade that facilitates the conversion of fibrinogen to fibrin while activating platelets and enhancing the coagulation process. In the treatment of cardiovascular diseases, inhibiting thrombin activity is a highly effective antithrombotic strategy. Thrombin inhibitors are widely used to manage conditions such as deep vein thrombosis (DVT), atrial fibrillation (AF), and acute coronary syndromes (ACS), offering critical benefits in preventing and treating thrombotic events.

Fig. 1 Blood coagulation cascade. The three-dimensional structures of prothrombin, thrombin, and its substrate. (Troisi R, et al., 2021)

Current Status of Thrombin Inhibitor Development

Thrombin inhibitors are a class of drugs that directly or indirectly block thrombin activity, playing a vital role in anticoagulation therapy for the prevention and treatment of thrombosis-related conditions. Some of the drug discovery pipelines of thrombin inhibitors are listed in the table below.

Thrombin Inhibitors in Development or Approved for the Treatment of Cardiovascular Diseases

Discovery of Thrombin Inhibitors

Based on our professional technology platform, we can help clients develop various types of thrombin inhibitors.

• Small Molecule Thrombin Drug
  Using computer-aided drug design technology, we screen and optimize small molecule candidates using molecular docking and molecular dynamics simulations. This approach accelerates the development of novel small molecule thrombin inhibitors with enhanced efficacy and specificity.
• Natural Peptide-Based Thrombin Inhibitors
  Natural peptide compounds derived from plants or marine organisms often exhibit potent antithrombin activity. We specialize in optimizing and modifying these peptides to develop thrombin inhibitory peptide with antithrombotic properties.

Discovery of Gene Silencing Therapies Targeting Thrombin

We develop innovative gene silencing therapies that target the mRNA of thrombin or related factors, reducing their expression to achieve therapeutic effects comparable to thrombin inhibitors.

Discovery of Monoclonal Antibodies Against Thrombin

To meet the specific needs of our clients, we support the development of monoclonal antibodies targeting thrombin. These biologics offer a highly specific and potent approach to thrombin inhibition.

In Vitro Pharmacodynamic Studies

• Thrombin Activity Assay
  We use recombinant human thrombin for fluorescent substrate analysis or colorimetric assay to determine the IC₅₀ value (half-maximal inhibitory concentration) of the test drug on thrombin.
• Coagulation Assay
  To evaluate direct thrombin inhibition, we measure key coagulation parameters such as thrombin time (TT) and activated partial thromboplastin time (APTT) under controlled in vitro conditions.
• Platelet Activation Assay
  We can assess the inhibition of thrombin-mediated platelet activation using flow cytometry to detect markers such as P-selectin (CD62P) and platelet GPIIb/IIIa activation levels.

In Vivo Pharmacodynamic Studies

• Effect on Thrombosis
  Depending on the need for efficacy evaluation, we can choose the right animal models of thrombosis to monitor the time of vascular occlusion and thrombus area, and to assess the inhibitory effect of the test drug on thrombus generation.
• Effect on Atherosclerosis
  Using ApoE-/- or LDL-R-/- mouse models, we investigate the impact of thrombin inhibitors on atherosclerotic plaque formation. These studies help elucidate the role of thrombin in atherosclerosis and evaluate the therapeutic potential of thrombin inhibitors in modulating disease progression.

Based on our dedicated research team and technology platform, Ace Therapeutics is committed to delivering end-to-end preclinical research services for thrombin inhibitor development, ensuring innovative and effective solutions for cardiovascular diseases. If you are interested in our services, please do not hesitate to contact us.

1. Troisi, R.; et al. Exosite binding in thrombin: A global structural/dynamic overview of complexes with aptamers and other ligands. Int J Mol Sci. 2021, 22(19):10803.