# Optimization of small molecule SERCA2b activators to inhibit neuron loss in Alzheimer's disease

> **NIH NIH R44** · NEURODON LLC · 2024 · $694,864

## Abstract

In this Phase IIB SBIR project for Alzheimer’s disease (AD) drug development, Neurodon LLC proposes to
conduct preclinical development and IND-enabling activities on our novel, orally available lead and backup
compounds that, in our preceding Phase II project, showed neuroprotection and beneficial effects on learning
and memory in a transgenic model of AD. Despite the enormity of AD as a national public health burden, the
therapeutic options are very limited. The few approved drugs treat only symptoms, and there are no disease-
modifying therapies available. All of the disease-modifying clinical trials have failed, with most drug targets
being amyloid or amyloid-related. With this patient population set to almost triple over the next 30 years, there
is an urgent need for disease-modifying therapies, specifically alternatives to amyloid-targeted drugs. Neuron
loss is the only physiological phenomena that has been directly linked to the cognition and memory loss in
patients, and a major cause of this brain cell loss in AD is endoplasmic reticulum (ER) stress-induced
apoptosis caused by aberrant intracellular Ca2+ homeostasis. Neurodon’s patented, small molecule activators
of the major ER Ca2+ handling protein, sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), correct neuronal
calcium handling, rescue brain cells in vitro and in vivo, improve learning and memory in the APP/PS1 double
transgenic mouse model of AD, and reduce ER stress and apoptosis markers in vivo, enabling biomarker-
driven drug discovery and an improved probability of clinical success. Our Phase II research met the
milestones of nominating orally active lead and backup compounds that show efficacy in an animal model of
AD. Our goal of delivering an IND for AD will be accomplished by pursuing the following Aims: 1) Chemistry
scale-up, pre-formulation, ADME, and PK on our lead SERCA2b activator and 2 backup compounds. 2) To
assess the effects of SERCA2b activators on cognition and profiling AD mechanism-specific biomarkers in
vivo. 3) Perform necessary preclinical studies on a selected SERCA2b activator new chemical entity (NCE)
and backup compound in preparation for IND filing. The results of these Aims will be the generation of efficacy,
safety, and CMC information to complete a submission-ready FDA IND application for a new, disease-
modifying therapeutic for AD.

## Key facts

- **NIH application ID:** 10934536
- **Project number:** 5R44AG062001-05
- **Recipient organization:** NEURODON LLC
- **Principal Investigator:** Russell Dahl
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $694,864
- **Award type:** 5
- **Project period:** 2018-09-30 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934536

## Citation

> US National Institutes of Health, RePORTER application 10934536, Optimization of small molecule SERCA2b activators to inhibit neuron loss in Alzheimer's disease (5R44AG062001-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10934536. Licensed CC0.

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