# Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics

> **NIH NIH R41** · MYRIEL, INC. · 2024 · $349,992

## Abstract

PROJECT ABSTRACT
Myriel, Inc., is a pharmaceutical start-up company founded in 2022 to find cures for tauopathies, including
Alzheimer’s disease and related dementias (ADRD), which impair cognition in 32% of US adults 65 years and
older. The goal of this Phase 1 STTR application is to provide Myriel with a brain-penetrant analogue of our lead
compound, GPHR ‘739, the first potent, selective, reversible Casp2 inhibitor that successfully reverses
pathologically depressed neurotransmission in a rodent model of ADRD. Inhibiting Casp2 is a highly promising
strategy for treating ADRD because Casp2-cleavage of the neuronal protein tau compromises synaptic and
cognitive function in models of several different ADRD, and preventing Casp2 from cleaving tau in this manner
restores synaptic function and reverses preexisting memory loss. Our central hypothesis is that prodrugs of
GPHR ‘739 in which its two negatively charged carboxylic acids are neutralized by esterification, cyclization,
and/or amidation to meet predetermined attributes for metabolic stability and membrane penetration will cross
the blood-brain-barrier, thereby qualifying them for future pharmacodynamic studies. Myriel will capitalize on the
co-PI’s (Walters) experience discovering brain-penetrant compounds and prodrugs that successfully completed
IND-enabling studies and reached clinical trials, and skillfully adapt strategies that produced a brain-penetrant
Casp2/3 inhibitor which improves ischemic brain injury in rats and a brain-penetrant Casp1 inhibitor that
advanced to Phase 2 clinical trials. We will achieve our goal of generating a brain-penetrant Casp2 inhibitor
through three specific aims: 1) esterification and amidation of diacid side-chains in GPHR ‘739; 2) cyclization of
diacid side-chains in GPHR ‘739; and 3) pharmacokinetic studies of five GPHR ‘739 analogues. Upon completion
of this project, we expect to have at least one prodrug of GPHR ‘739 that penetrates into the brain to prespecified
levels, thus poising it for future IND-enabling studies. These results will significantly advance Myriel’s progress
toward developing a Casp2-inhibiting drug that reduces the prevalence of impaired cognition in the elderly.

## Key facts

- **NIH application ID:** 10932200
- **Project number:** 5R41NS134497-02
- **Recipient organization:** MYRIEL, INC.
- **Principal Investigator:** Karen H Ashe
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $349,992
- **Award type:** 5
- **Project period:** 2023-09-20 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932200

## Citation

> US National Institutes of Health, RePORTER application 10932200, Prodrugs of potent and selective protease inhibitors as tauopathy therapeutics (5R41NS134497-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10932200. Licensed CC0.

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