# Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment

> **NIH NIH U01** · NORTHWESTERN UNIVERSITY · 2022 · $1,516,817

## Abstract

ABSTRACT
Alzheimer's disease and related dementias (AD/ADRD) have a significant societal impact, yet there are no
disease modifying interventions. Root causes of prior clinical trial failures provide instruction for plans to
reinvigorate the AD/ADRD therapeutic discovery and development process. Specifically, a diversified portfolio
of candidate therapeutic approaches is available based on clinical observations, genetic associations,
pathology outcomes and biochemical mechanisms. However, many are neglected in terms of funding and
technical pursuit. The prior emphasis on a pathology-based pathway can be avoided by retaining a therapeutic
emphasis on discrete but complementary aspects of pathophysiology progression mechanisms. Synaptic
dysfunction is one example with diverse potential targets. Synaptic dysfunction underlies subtle amnesic
changes occurring prior to the development of the classical histopathologic hallmarks. Deteriorated synaptic
strengthening is associated with remodeling of various neurotransmitter systems, including cholinergic,
noradrenergic, dopaminergic and serotonergic systems. The serotonergic system is both an underexplored
therapeutic mechanism and is especially attractive considering that serotonin is more than a neurotransmitter.
Further, clinical findings that 5-hydroxytryptamine receptor 2b (5-HT2bR) expression is increased in AD patient
brains and that AD patients respond to a non-selective 5-HT2bR antagonist suggest the potential utility of
optimized 5-HT2bR antagonists in AD. We developed a small molecule, MW01-8-071HAB (=MW071), that
suppresses LTP defects as well as associative and spatial memory in models of amyloid-beta (Aβ) and tau
elevation. Functional screens for off-target agonist and antagonist activity with 158 known GPCRs
demonstrated that MW071 is a selective 5-HT2bR antagonist. Importantly, MW071 lacks 5-HT2BR agonist
activity. Avoiding agonist activity is landmark. Approved drugs with 5-HT2bR agonist activity have high risk for
cardiac valve toxicity, resulting in withdrawal or black box warnings. Therefore, the promising efficacy in AD
relevant models, a pharmacological profile that includes highly selective antagonist activity in the absence of
agonist activity, and the availability of a back-up candidate (MW109) adds to the overall appeal of MW071 as a
starting point. Our proposed early-stage studies will further de-risk MW071 and MW109 in order to generate
and qualify a candidate for a future IND-enabling late stage U01 application:
Aim 1. Perform secondary pharmacology analyses following FDA guidance, as a necessary prelude and a firm
foundation for future GxP IND-enabling preclinical safety and toxicology research.
Aim 2. Validate the efficacy of MW071 and MW109 in prevention/reversal of synaptic and memory
impairments in AD-relevant animal models.
Quantitative milestones will determine progression through Go/No Go decision points. Successful outcomes
and deliverables will allow for future suppo...

## Key facts

- **NIH application ID:** 10396647
- **Project number:** 5U01AG066722-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** OTTAVIO ARANCIO
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,516,817
- **Award type:** 5
- **Project period:** 2020-05-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10396647

## Citation

> US National Institutes of Health, RePORTER application 10396647, Preclinical development of a novel small molecule inhibitor of Alzheimer's disease-related cognitive impairment (5U01AG066722-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10396647. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*