# Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease

> **NIH NIH U01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $1,403,321

## Abstract

Neuroinflammation has been recognized as an essential player in the pathogenesis of Alzheimer’s
disease (AD). Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, a
multimeric protein complex that tightly regulates the innate immune responses, has been suggested with
critical roles in AD development and progression. Dysregulation of the NLRP3 inflammasome is responsible for
the over production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory
responses and cell death. Thus, NLRP3 inflammasome represents an attractive drug target for AD and offers
promise to provide effective disease modifying potential. Over the past several years, our team has
successfully developed novel small molecule NLRP3 inflammasome selective inhibitors (NSIs). We originally
reported NSIs with sulfonamide containing chemical scaffolds, and have established a small molecule library
containing > 200 compounds with various biological characteristics. Proof of concept studies of our 1st
generation lead NSI in transgenic AD mouse models demonstrated target engagement and in vivo efficacy to
reduce neuroinflammation and improve cognitive functions. Our recent medicinal chemistry campaign led to
the identification of new lead NSIs with significantly improved potency and binding affinity. Furthermore, our
accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds
for further optimization. The central hypothesis of this proposal is that structural optimization of the current two
preclinical lead NSIs will be achieved by designing new viable analogs and isolating potent and orally available
NSIs with improved pharmacokinetic (PK) properties (Aim 1), and that pharmacological suppression of the
NLRP3 inflammasome by our NSIs will mitigate neuroinflammation and improve cognitive functions in
preclinical AD animal models (Aim 2), which will be further evaluated by preclinical Investigational New Drug
(IND)-enabling studies (Aim 3) to advance to clinical studies. For our hypothesis, the goal of this application is
to accomplish preclinical IND-enabling studies on at least one candidate NSI and prepare for a meeting with
the FDA and subsequent IND filing. Three aims are proposed to achieve our objectives. In Aim 1, new analogs
of the lead NSIs will be designed, synthesized and biologically characterized to build a dynamic drug discovery
and development pipeline. In Aim 2, selected NSIs from aim 1 will be tested for PK/PD properties in various
animal models including AD mouse models. In aim 3, the top candidate NSI identified from Aim 2 will be
subjected to IND-enabling studies including GMP production, GLP toxicology studies in rodents and dogs, and
oral formulation development to prepare for IND filing and clinical trials. The proposed research is highly
significant because we are developing a novel class of NSIs that will offer great promise to provide novel and
...

## Key facts

- **NIH application ID:** 10863986
- **Project number:** 5U01AG076481-03
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Shijun Zhang
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,403,321
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863986

## Citation

> US National Institutes of Health, RePORTER application 10863986, Development of novel NLRP3 inflammasome inhibitors for intervening in Alzheimer's disease (5U01AG076481-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10863986. Licensed CC0.

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