# Development of neutral sphingomyelinase 2 (nSMase2) inhibitors for the treatment of Alzheimer's disease

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $683,930

## Abstract

PROJECT SUMMARY
Neutral sphingomyelinase 2 (nSMase2 encoded by SMPD3 gene) is a membrane associated enzyme that
catalyzes the hydrolysis of sphingomyelin (SM) into phosphorylcholine and ceramide. Formation of ceramide-
enriched areas by the action of nSMase2 is known to facilitate generation of extracellular vesicles, which
participate in intercellular communication in both physiological and pathological processes through
encapsulation and transfer of diverse types of substances including tau protein. Interestingly, post-mortem brains
from AD patients exhibit abnormal increases in ceramide. Inhibition of nSMase2 has therefore become an
attractive therapeutic strategy to treat AD by inhibiting EV biogenesis to slow the spread of pathogenic cargo.
The main objective of this project is to conduct structural optimization using (R)-(1-(3-(3,4-dimethoxyphenyl)-2,6-
dimethylimidazo[1,2-b]pyridazin-8-yl)pyrrolidin-3-yl)-carbamate (PDDC), a prototype nSMase2 inhibitor, as a
molecular template with the ultimate goal of identifying development candidates with balanced overall
pharmacological profiles required for clinical translation. By assembling a multidisciplinary team of investigators
with complementary expertise, we are poised to seize this opportunity by executing the following specific aims;
(Aim 1) Conduct structure-activity relationship (SAR) studies on nSMase2 inhibitors containing a core scaffold
different from that of PDDC; (Aim 2) Characterize the ADME (absorption, distribution, metabolism and excretion)
and in vitro selectivity/toxicity profile of potent nSMase2 inhibitors from Aim 1. Identify optimal dosing for efficacy
studies in Aim 3; (Aim 3) Evaluate selected nSMase2 inhibitors from Aim 2 for efficacy and tolerability in an AAV
tau propagation model and a PS19 transgenic model of AD.

## Key facts

- **NIH application ID:** 10936519
- **Project number:** 5R01AG084728-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Rana Rais
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,930
- **Award type:** 5
- **Project period:** 2023-09-30 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10936519

## Citation

> US National Institutes of Health, RePORTER application 10936519, Development of neutral sphingomyelinase 2 (nSMase2) inhibitors for the treatment of Alzheimer's disease (5R01AG084728-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10936519. Licensed CC0.

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