Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?

Simeng Li,Justin R Hamilton,Volga Tarlac

doi:10.3390/ijms20225629

Abstract

Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar—the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions.

Highlights

Cardiovascular disease is the leading cause of death in the world, predominantly because of the prevalence of heart attacks and occlusive strokes
Aspirin and P2Y12 receptor antagonists are the leading agents for long-term preventative therapy yet prevent fewer than 20% of recurrent thrombotic events even when used in combination [1], phosphodiesterase inhibitors have a number of problematic side effects, such as arrhythmia [2], the αIIbβ3 antagonists all require intravenous administration and cause substantial bleeding, which precludes their use as long term preventatives [3,4,5], and vorapaxar causes an unacceptably high bleeding risk in several patient groups when administered in combination with aspirin and/or clopidogrel [6,7,8]
We review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions

Summary

Introduction

Cardiovascular disease is the leading cause of death in the world, predominantly because of the prevalence of heart attacks and occlusive strokes. Sci. 2019, 20, 5629 kinetics of the two receptors: PAR1 activation drives a rapid initial signal, whereas PAR4 activation induces a slower, but more prolonged response In platelets, such distinct signalling appears to underlie distinct functions. Selective activation of PAR1 is capable of inducing several of these responses, suggesting a level of redundancy in PAR-mediated platelet signalling [23,24], inhibition of PAR4 appears a more effective strategy to impair these later-stage platelet events than inhibition of PAR1 [18,22] This increased efficacy of PAR4 antagonism may provide a distinction over targeting PAR1 by acting at a later time and place and by interfering with unique platelet functions (Figure 2)

Why Target PAR4 for Anti-Thrombotic Therapy?

How Can

When Can We Best Target PAR4?

What Are the Major Issues to Consider for PAR4 Inhibitors?

Findings

Conclusions