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Development of Spleen Tyrosine Kinase (SYK) negative allosteric modifiers for therapeutic intervention in Alzheimer's disease.

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 4R42AG062063-02
Agency Tracking Number: R42AG062063
Amount: $1,511,397.00
Phase: Phase II
Program: STTR
Solicitation Topic Code: NIA
Solicitation Number: PAS18-188
Timeline
Solicitation Year: 2018
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-05-01
Award End Date (Contract End Date): 2022-04-30
Small Business Information
2040 WHITFIELD AVE
Sarasota, FL 34243-3922
United States
DUNS: 948616235
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 MICHAEL MULLAN
 (941) 752-2949
 mmullan@archerpharma.com
Business Contact
 LAUREN HORNE
Phone: (941) 755-6644
Email: coordinator@archerpharmaceuticals.com
Research Institution
 RESEARCH TRIANGLE INSTITUTE
 
BOX 12194, 3040 E CORNWALLIS RD
RESEARCH TRIANGLE PARK, NC 27709-2194
United States

 Domestic Nonprofit Research Organization
Abstract

Pathological hallmarks of Alzheimerandapos;s disease (AD) include extracellular deposits of Aβ peptides, intraneuronal
aggregates of abnormally phosphorylated tau protein and neuroinflammation. Most proposed AD disease
modifying therapies have focused on strategies that reduce brain Aβ/amyloid or tau pathological accumulation.
However, such approaches have been unsuccessful in late stage AD clinical trials and may only be most
useful as prophylactics, leaving millions of AD patients without therapeutic options. There is therefore a critical
need to evaluate therapeutic targets downstream of Aβ/amyloid and tau pathologies. We have determined that
the spleen tyrosine kinase (SYK) is pathologically activated in neurons and microglia both in AD patients and in
AD preclinical mouse models, and colocalizes with AD pathological hallmarks, suggesting SYK is a
downstream target of Aβ and tau pathologies. We have identified that nilvadipine, a known antihypertensive
dihydropyridine (DHP), that improves cognition and reduces the development of AD pathological hallmarks
including neuroinflammation in AD preclinical models, mediates its AD effects via an allosteric inhibition of SYK
highlighting SYK as a therapeutic target for AD. We have recently concluded a large randomized, double-
blind, placebo-controlled phase III trial of nilvadipine in mild to moderate AD revealing that nilvadipine has
cognitive benefits for mild, particularly very mild, AD in whom it slows the rate of cognitive decline. The main
goal of these studies is the development of a selective SYK negative allosteric modulator (NAM), more potent
than nilvadipine, for the treatment of AD without the blood pressure lowering effects. As the orthosteric site
configuration is conserved among kinases, which can lead to a lower specificity of a drug, resulting in adverse
side effects, we elected a drug discovery strategy exploiting SYK allosteric sites to lead to more selective
therapeutic agents. In this Fast Track STTR application, Phase I will allow the identification of a suitable SYK
NAM scaffold for drug development and the establishment of computational models to orient the rational
design and synthesis of novel SYK NAMs. Phase II will improve the SYK inhibitory activity and optimize the
ADME (Absorption, Distribution, Metabolism, and Excretion) properties of the SYK NAM scaffolds to identify an
advanced SYK NAM scaffold lead. The efficacy of the lead SYK NAM will be ultimately explored in preclinical
models of AD exhibiting Aβ, tau and inflammatory pathologies. Given our previous preclinical data obtained
with nilvadipine and another selective SYK inhibitor (BAY61-3606), we anticipate that targeting SYK with a
SYK NAM should alleviate some of the downstream consequences of Aβ and tau accumulation including
neuroinflammation, synaptic loss and neurodegeneration, and should also reduce the propagation of the tau
pathology and Aβ/amyloid accumulation. The SYK NAM scaffolds that we are developing have the potential to
simultaneously affect neuroinflammatory processes, Aβ/amyloid and tau pathologies and may lead to more
effective AD treatments than targeting a single pathological aspect of the disease.Alzheimerandapos;s disease (AD) is an ever-increasing health concern among the aging
population and is the most common form of dementia affecting nearly 50 million
individuals worldwide, with no effective disease-modifying therapies and many clinical
failures of therapeutics focused solely on amyloid or tau pathologies.
Drugs with multi-modal action are an alternative strategy to treat the disease, and our
lead compound, nilvadipine, is a demonstrably safe small molecule dihydropyridine
(DHP), with anti-amyloid, anti-tau and anti-inflammatory characteristics, which has
recently demonstrated efficacy in an exploratory subset of very mild AD patients from
our Phase III trial.
Nilvadipineandapos;s anti-Alzheimer activity is through inhibition of the spleen tyrosine kinase
(SYK), and in this proposal we will develop and screen negative allosteric SYK
modulators, based on DHP and related scaffolds, with greater potency, specificity and
preclinical efficacy, to advance to AD clinical trials.

* Information listed above is at the time of submission. *

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