Inhibitors of protease-activated receptor 4 (PAR4): a review of recent patents (2013–2021)

ABSTRACT

Introduction

Protease-activated receptor 4 (PAR4), belonging to a subfamily of G-protein-coupled receptors (GPCR), is expressed on the surface of Human platelets, and the activation of it can lead to platelets aggregation. Studies demonstrated that PAR4 inhibition protect mice from arterial/arteriolar thrombosis, pulmonary embolism and cerebral infarct, while do not affect the hemostatic responses integrity. Therefore, PAR4 has been a promising target for the development of anti-thrombotic agents.

Areas covered

This review covers recent patents and literature on PAR4 and their application published between 2013 and 2021.

Expert opinion

PAR4 is a promising anti-thrombotic target and PAR4 inhibitors are important biologically active compounds for the treatment of thrombosis. Most the recent patents and literature focus on PAR4 selective inhibitors, and BMS-986120 and BMS-986141, which were developed by BMS, have entered clinical trials. With the deep understanding of the crystal structures and biological functions of PAR4, we believe that many other novel types of molecules targeting PAR4 would enter the clinical studies or the market.

KEYWORDS:

• Protease-activated receptor 4
• PAR4
• small-molecule antagonists
• antibody
• anti-thrombosis
• anti-platelet

Article highlights

• PAR4 is a promising target for the treatment of thrombosis disease.

• Six functional regions in PAR4 are indicated.

• Two IDTs PAR4 inhibitors BMS-986120 and BMS-986141 have entered clinical stage.

• Quinoxaline analogues are promising PAR4 inhibitors.

• PAR4 biological macromolecular inhibitors are described.

This box summarizes key points contained in the article.

Declaration of interests

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 options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has disclosed that several of the patents described in this paper come from their research group. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This research was funded by China Pharmaceutical University initiative program (no. CPU2018GY15).