# Targeting PAR4 in Thrombotic Disorders:Pharmacogenomic Approach

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $754,865

## Abstract

PROJECT SUMMARY
Though deaths from heart disease and stroke have fallen dramatically in the last 40 years, these thrombotic
diseases are still our largest killer. The overall goal of this grant is to develop a new class of anti-platelet
compounds for managing the risk and treatment of thrombosis. Platelets play a critical role in thrombosis, the
major cause of mortality and morbidity. Medical management of acute coronary syndrome and cerebrovascular
injury is centered on anti-platelet therapies. Thrombin is an essential activator of protease activated receptors
(PAR) in platelets for generation of a hemostatic plug. Human platelets have both PAR1, the high-affinity
thrombin receptor that underlies hemostasis at the vessel wall, and PAR4, the low-affinity thrombin receptor
which is activated slowly in the clot because it requires substantial thrombin build up. Our guiding hypothesis
is that PAR4 is an attractive target for anti-platelet therapy in thrombosis and cerebrovascular injury, because
of its local activation at the site of the 3D clot as more thrombin builds up. We hypothesize that PAR4
antagonism might minimize clot build-up in the vessel, but not affect hemostasis as potently and thus may
decrease bleeding side effects and be a better therapeutic anti-platelet target. Blacks have a significantly
higher incidence of heart disease and stroke and worse survival. Recently, a hyperactive PAR4 allele was
discovered and found to occur in 63% of blacks but only 16% of whites. We have used HTS and medicinal
chemistry to obtain nM and pM affinity antagonists of PAR4 which block both alleles. We propose to optimize
bioavailability, potency, and selectivity of our lead molecules for both of these PAR4 alleles and test them in a
baboon shunt model of thrombosis. We will 1) optimize the best series of PAR4 antagonists using a library
approach, 2) determine selectivity and potency of compounds, and carry forward compounds that have diverse
modes of action to maximize safety 3) determine the pharmacokinetics, metabolism and disposition of these
PAR4 antagonists in vitro in baboon and human and in vivo in baboon, and 4) test the optimized compound in
human platelets under flow and in a baboon shunt model of thrombosis. Completion of these aims will provide
evidence in primate models of thrombosis that PAR4 antagonism is safe and efficacious. The long-term goal is
to demonstrate PAR4 as an alternative target for preventive and therapeutic suppression of pathologic
thrombus formation. An antagonist that is active against the hyperactive PAR4 allele may have the potential to
develop into an ideal anti-platelet agent that can decrease the racial disparity of outcomes of thrombotic
events.

## Key facts

- **NIH application ID:** 9900857
- **Project number:** 5R01HL133923-04
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** HEIDI E HAMM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $754,865
- **Award type:** 5
- **Project period:** 2017-04-01 → 2021-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9900857

## Citation

> US National Institutes of Health, RePORTER application 9900857, Targeting PAR4 in Thrombotic Disorders:Pharmacogenomic Approach (5R01HL133923-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9900857. Licensed CC0.

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