# Novel Analogs for Tauopathies and Their Mode of Action

> **NIH NIH R36** · UNIVERSITY OF RHODE ISLAND · 2020 · $69,485

## Abstract

Project Abstract and Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease and is considered the predominate cause
of dementia worldwide. In the United States (US), it is the sixth leading cause of death. It results in a loss of
memory, thinking skills and task performance. The pathological hallmarks of AD are accumulated amyloid β
(Aβ) plaques and neurofibrillary tangles (NFTs). Studies have shown that reduction in wild-type tau prevents
Aβ-dependent behavioral and cognitive deficits, suggesting that therapeutic interventions that alter the levels of
tau may be beneficial. Our lab provided convincing evidence that either silencing the Sp1 gene, using small
interfering RNA, or treatment of animals with Tolfenamic Acid (TA), lowers the expression of AD-related Sp1
target genes. TA (Clotam® Rapid) is currently used in Europe and other countries to treat symptoms of migraine
headaches. TA serves as an excellent candidate for the design and synthesis of novel derivatives. Thus, we
synthesized a series of analogs using the lead compound scaffold by focusing on optimizing potency, selectivity,
and generating drug-like molecules for CNS delivery, while, also, honing the physical properties of the
compounds. Furthermore, we aimed to decrease the COX-related action of these compounds and enhance their
targeting of Sp1/tau. We, now, have a series of compounds and we would like to examine: efficacy, potency,
cytotoxicity, potential mechanism of action, selectivity and off target effects in an in vitro cell culture model. The
following are the aims of the proposal: 1) Investigate the ability of analogs, with a better safety profile than TA,
to lower the mRNA and protein levels of total tau, site specific tau phosphorylation, CDK5, Sp1, and COX2, in
an in vitro model, 2) Testing of lead analogs for mode of action and target engagement, 3) Analyze the brain
transfer potential of TA analogs using in silico and in vitro approaches. The expected outcomes are that we will
find that TA analogs specifically target Sp1 and other related biomarkers by chelating Zn. We, also, expect that
the analogs will cross the blood brain barrier (BBB) due to structural and physiochemical characteristics that
enhance brain penetration potential.

## Key facts

- **NIH application ID:** 9914963
- **Project number:** 5R36AG062868-02
- **Recipient organization:** UNIVERSITY OF RHODE ISLAND
- **Principal Investigator:** Jaunetta Hill
- **Activity code:** R36 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $69,485
- **Award type:** 5
- **Project period:** 2019-04-15 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914963

## Citation

> US National Institutes of Health, RePORTER application 9914963, Novel Analogs for Tauopathies and Their Mode of Action (5R36AG062868-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9914963. Licensed CC0.

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