Contemporary medicinal-chemistry strategies for discovery of blood coagulation factor Xa inhibitors

ABSTRACT

Introduction: Thrombosis is a common causal pathology for stroke, acute coronary syndrome and venous thromboembolism disorders, which are the leading cause of death worldwide. Anticoagulants have exhibited a crucial role in the prevention and treatment of thrombotic diseases. Factor Xa (FXa) is a serine protease with a central role in activating the complex blood coagulation cascade, and it is therefore regarded as an attractive target for antithrombotic agents.

Areas covered: The authors review the current status of medicinal chemistry strategies for the discovery of novel FXa inhibitors and provide their expert perspectives on their future development.

Expert opinion: Even if only a number of small-molecule FXa inhibitors have been reported to date, all currently available FXa inhibitors are associated with significant risk of bleeding, which may become life-threatening. There is, therefore, an urgent and unmet demand for potent novel FXa inhibitors that are potent treatments for thrombotic disorders, but which have a reduced risk of bleeding if their use is to be increasingly favored.

KEYWORDS:

• FXa
• anticoagulants
• synthetic inhibitors
• medicinal chemistry strategies
• drug design

Article highlights

• Factor Xa (FXa) has become a promising target for anticoagulation effects.

• The X-ray-based structural bioinformatics are being applied increasingly in the discovery of FXa inhibitors.

• Traditional medicinal chemistry strategies play a crucial role in the structural modification of FXa inhibitors.

• The past several years have realized a large number of publications describing new advances in the discovery of novel FXa inhibitors.

• It is still imperative to discover novel factor Xa inhibitors with better therapeutic windows via contemporary medicinal chemistry strategies.

This box summarizes key points contained in the article.

Acknowledgments

All figures showing binding modes were generated using PyMol (www.pymol.org).

Declaration of interest

The authors have no other 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 apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

Supplemental data can be accessed here.

Additional information

Funding

We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC Nos. 81573347, 81603028), the Young Scholars Program of Shandong University (YSPSDU No. 2016WLJH32), the Fundamental Research Funds of Shandong University (No. 2017JC006), Key Project of NSFC for International Cooperation (No. 81420108027), the Natural Science Foundation of Shandong Province (No. ZR2016HB26), and the Key research and development project of Shandong Province (No. 2017CXGC1401).