# Small Molecule PAR1 Ligands for the Treatment of MASH

> **NIH NIH R43** · FUNCTION THERAPEUTICS, INC. · 2024 · $463,714

## Abstract

PROJECT SUMMARY
Metabolic dysfunction-associated steatohepatitis (MASH, formerly NASH) is a liver disease characterized by
the unnatural accumulation of lipids within hepatic cells, inflammation, and ultimately fibrosis. It is frequently
connected to obesity and estimated to affect up to 5% of adults in the U.S., and despite huge investments by
the pharmaceutical industry, there are not (yet) any FDA-approved drugs for MASH. Anti-inflammatory
compounds are relatively under investigated for this disease, and may have the potential to minimize the
dangerous liver fibrosis that occurs as MASH progresses.
This project will investigate a novel approach to the treatment of MASH: the induction of anti-inflammatory
signals in liver tissue via biased small molecule modulators of protease-activated receptor 1 (PAR1), called
parmodulins. Published and unpublished results using wild-type and PAR1-modified mice fed high-fat diets
(HFD) suggest that inflammatory effects of MASH are lessened with a natural activator of PAR1, activated
protein C (APC), and also by compounds that can block the inflammatory signaling initiated by the activation of
PAR1 by thrombin (i.e., thromboinflammation). In this project, we will test the ability of orally-active
parmodulins to produce protective effects in mice by tipping the balance of PAR1 signaling in liver tissue from
a pro-inflammatory to an anti-inflammatory phenotype.
In Aim 1, novel parmodulins will be synthesized that have been designed to lack the potential to generate toxic
metabolites, and which may possess improved potency at PAR1. In Aim 2, these compounds will be tested in
cellular models of PAR1 signaling and inflammation, and promising examples will be studied in a series of
standard drug-like profiling assays, including cytotoxicity, solubility, plasma and metabolic stability, and off-
target activity. In Aim 3, select parmodulins will undergo PK studies, and representative examples will progress
to a mouse model of advanced MASH in the lab of co-investigator Dr. James Luyendyk (Michigan State Univ.).
Mice with a high fat, high cholesterol, and high sugar diet will be dosed with carbon tetrachloride to induce an
advanced form of MASH with significant fibrosis. Mice will then be treated with parmodulins at high and low
doses to determine their ability to inhibit a range of measures of liver injury, steatosis, inflammation, and
fibrosis. It is anticipated that parmodulins will have minimal bleeding risks relative to certain thrombin inhibitors
and PAR1 antagonists, and this will be supported with a guinea pig hemostasis study.
Successful results in these studies will justify the completion of lead optimization and the future preclinical
development of parmodulins for the treatment of MASH and potentially other liver diseases.

## Key facts

- **NIH application ID:** 11007625
- **Project number:** 1R43DK141373-01
- **Recipient organization:** FUNCTION THERAPEUTICS, INC.
- **Principal Investigator:** Christopher Dockendorff
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $463,714
- **Award type:** 1
- **Project period:** 2024-08-15 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007625

## Citation

> US National Institutes of Health, RePORTER application 11007625, Small Molecule PAR1 Ligands for the Treatment of MASH (1R43DK141373-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11007625. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*