# Discovery of Drugs that Modulate Neuroinflammation for the treatment of Alzheimer's Disease

> **NIH NIH U01** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $1,770,176

## Abstract

Discovery of Drugs that Modulate Neuroinflammation for the Treatment of Alzheimer's Disease
Project Summary/Abstract (30 lines)
Alzheimer’s disease (AD) is the primary cause of dementia in the elderly. At present, approximately 36 million
people worldwide suffer with AD, and that number is expected to increase to about 120 million by 2040. Despite
decades of intense research, currently there are only four FDA-approved drugs to treat AD symptoms. These
drugs, however, do not prevent, stop or slow the progression of the disease.
Inflammation is considered a crucial link between Aβ plaques, NFTs and AD. Therefore, the modulation of pro-
inflammatory cytokines may be a viable approach to treat AD. In a screen to identify small molecule modulators
of inflammation, we identified a promising lead that has modest affinity for both the GABAA and TSPO receptors.
The preliminary SAR and data suggest that the anti-inflammatory effect derives from a combination of both
GABAA and TSPO activities. Continued optimization of both the pharmacodynamic and pharmacokinetic
properties of the lead will result in a significantly improved molecule that has the potential to treat both (i) cognitive
deficits and (ii) anxiety and aggression in AD. The specific aims to achieve this goal are:
Aim 1. In vivo proof of concept studies of etifoxine in two mouse models of AD. Etifoxine has demonstrated
beneficial effects in several neurodegenerative disease models; however, it was not tested in mouse models of
AD or in human AD patients. Therefore, we will evaluate the efficacy of etifoxine in (i) the rTG4510 (Tau
pathology) and (ii) the APP/PS1 (amyloid plaque) mouse models of AD.
Aim 2. Medicinal chemistry optimization and characterization of novel analogs of etifoxine. Single
enantiomer analogs of etifoxine will be designed, synthesized and characterized in biological assays. The most
promising compounds will be evaluated in drug-like property and PK studies. Compounds with appropriate PK
and brain exposure will advance into in vivo studies to measure target engagement (e.g., stimulation of
pregnenolone in mouse brain). Lead compounds also will be tested for sedative effects, and those that have
sedative potential will be deprioritized.
Aim 3. In vivo efficacy of the lead molecule in the rTG4510 mouse model of AD. We will evaluate the effects
of three different doses of the lead compound in the rTG4510 mouse model (as described in Aim 1), Treatment
will begin at 2 months (onset pathology), and end at 5 months (start of cognitive decline). The goal is to
demonstrate efficacy on multiple measures including inflammation, synaptic integrity, neurodegeneration, tau
pathogenesis, memory and learning.
Aim 4. Pre-IND enabling studies; scale-up synthesis, multi-species PK, and rodent toxicity. The goal is to
determine if the lead compound has any liabilities that would preclude its further development. The lead will be
tested in a battery of industry standard in vitro DMPK and in vitro t...

## Key facts

- **NIH application ID:** 10052276
- **Project number:** 1U01AG066759-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Kevin Hodgetts
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,770,176
- **Award type:** 1
- **Project period:** 2021-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10052276

## Citation

> US National Institutes of Health, RePORTER application 10052276, Discovery of Drugs that Modulate Neuroinflammation for the treatment of Alzheimer's Disease (1U01AG066759-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10052276. Licensed CC0.

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