# Optimization of microtubule-stabilizing triazolopyrimidines as therapeutics for Alzheimer's disease and related tauopathies

> **NIH NIH U01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $946,116

## Abstract

PROJECT SUMMARY
A group of neurodegenerative diseases referred to as tauopathies, which includes Alzheimer’s disease (AD), are
characterized by the presence within brain neurons of inclusions comprised of hyperphosphorylated forms of
tau protein. Tau is normally a microtubule (MT)-associated protein that appears to provide stability to MTs in
axons, and excessive phosphorylation of tau in tauopathies promotes its disengagement from MTs and
misfolding into oligomeric and fibrillar structures. This results in increased MT dynamicity, reduced MT density
and altered axonal transport in transgenic (Tg) mouse tauopathy models, with evidence of similar MT deficits in
AD brain that likely contribute to neurodegeneration. We previously demonstrated that administration of the
brain-penetrant MT-stabilizing natural product, epothilone D (EpoD), to Tg tauopathy mice resulted in dramatic
improvements in several key endpoints, including increased MT density, reduced axonal dystrophy, diminished
tau pathology and a lowering of neuron loss with improved cognitive performance. Although EpoD progressed
to a small Phase 1b clinical trial in AD patients, its future clinical advancement is uncertain. Thus, there would
be considerable value in identifying alternative MT-stabilizing agents that could undergo more thorough testing
in AD and tauopathy patients. In this regard, we have synthesized and evaluated a series of non-natural product
MT-stabilizing compounds (triazolopyrimidines or TPDs, and phenylpyrimidines), and an evaluation of these
compounds has led to an understanding of key structure-activity correlates. An assessment of pharmacokinetic
(PK) and pharmacodynamics (PD) profiles of select examples resulted in the identification of a lead TPD that
has recently shown highly beneficial activity in a Tg mouse tauopathy model. We propose in this early-stage U01
program to utilize lessons learned in our initial medicinal chemistry exploration to conduct a highly focused
chemical optimization program to identify a candidate TPD compound suitable for entry into IND-enabling pre-
clinical safety pharmacology and toxicology studies. We will utilize in silico computational docking studies to
select and prioritize patentable TPD congeners for activity testing in established cellular assays. Data from these
studies will be utilized to refine the scoring method and re-evaluate the prioritization of in silico hits, leading to
additional iterative cycles of synthesis and biological evaluations. The most active compounds identified through
this process will be assessed for brain exposure in mice, and preferred examples will undergo complete PK and
PD testing. Ultimately, a select few analogs with superior PK/PD properties will be assessed for
safety/tolerability in mice, with the best candidate advancing to efficacy studies in an established Tg mouse
tauopathy model. The overall project objective is to identify a patentable lead candidate TPD that would be
eligible for entry...

## Key facts

- **NIH application ID:** 9875440
- **Project number:** 5U01AG061173-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** KURT R. BRUNDEN
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $946,116
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875440

## Citation

> US National Institutes of Health, RePORTER application 9875440, Optimization of microtubule-stabilizing triazolopyrimidines as therapeutics for Alzheimer's disease and related tauopathies (5U01AG061173-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9875440. Licensed CC0.

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