Discovery methods of coagulation-inhibiting drugs

ABSTRACT

Introduction: In the last decade, several direct oral anticoagulants (DOAC) targeting thrombin (dabigatran) or activated factor X (FXa) (rivaroxaban, apixaban and edoxaban) have been marketed for a number of indications related to prophylaxis and treatment of thrombotic diseases. All these drugs are effective in preventing thrombosis, but are associated with an increased bleeding risk.

Areas covered: This review includes a summary of new targets for anticoagulation (e.g.: FXIa, FXIIa, protein disulfide isomerase, polyphosphates, etc.), the discovery process and pharmacological features of new anticoagulant compounds and the available results from non-clinical and clinical studies. A significant number of new anticoagulant compounds are currently in development. These compounds were developed using different technologies like SELEX (aptamers), antisense technology (ASOs), hybridoma (MAB) and structure based drug design. Compounds like ichorcumab (a parenteral thrombin inhibitor), BMS-986177 (oral FXIa inhibitor), BAY-1213790 and xisomab (parenteral FXIa inhibitors) are currently in the clinical development stage.

Expert opinion: It’s important to be cautious when interpreting preliminary findings of new compounds showing a good antithrombotic effect without altering haemostasis. That being said, the anticoagulants in development have the potential to provide a safer alternative to the currently available anticoagulants in patients at high risk of bleeding, but further investigation is warranted.

KEYWORDS:

• Stroke
• anticoagulant
• discovery
• thrombosis
• bleeding

Article highlights

• The direct oral anticoagulants (DOACs) targeting thrombin or activated factor X (FXa) have shown a halved risk of major bleeding compared with warfarin, but major bleeding rates are still significant.

• A variety of compounds of heterogeneous chemical classes with anticoagulant activity (e.g.: aptamers, ASOs, MABs, synthetic pentasaccharides, small compounds, vaccines and anticoagulant proteins) are currently in development.

• These compounds were inspired by observations in humans (e.g.: congenital or acquired deficiencies of coagulation factors, epidemiological studies, etc.) and animals (e.g.: anticoagulant proteins from snake venom), and developed using different technologies like SELEX (aptamers), antisense technology (ASOs), hybridoma (MAB), or structure based drug design (SBDD).

• Ichorcumab (parenteral thrombin inhibitor), BMS-986177 (oral FXIa inhibitor), BAY-1213790 and xisomab (parenteral FXIa inhibitors) are currently in clinical development stage.

• The novel anticoagulants in development have the potential to provide a safer alternative than currently available anticoagulants in patients at high risk of bleeding, but further investigation is warranted.

This box summarizes key points contained in the article.

Acknowledgment

The opinions expressed in this review are of the authors alone and they do not necessarily represent the view of their institution or any other party.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or opinions, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This manuscript was not funded.