Drug regulators of nitric oxide production as Alzheimer's disease therapeutics

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$726,746.00
Award Year:
2012
Program:
STTR
Phase:
Phase I
Contract:
1R41AG043243-01
Award Id:
n/a
Agency Tracking Number:
R41AG043243
Solicitation Year:
2012
Solicitation Topic Code:
NIA
Solicitation Number:
PAR09-259
Small Business Information
10225 Barnes Canyon Road suite A104, SAN DIEGO, CA, -
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
963248807
Principal Investigator:
JOHNSCHETZ
(817) 735-2064
jschetz@hsc.unt.edu
Business Contact:
FABIOTUCCI
(619) 917-0639
ftepigen@gmail.com
Research Institute:
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON

UNIVERSITY OF TEXAS HLTH SCI CTR
BOX 20036
HOUSTON, TX, 77225-
() -

Abstract
DESCRIPTION (provided by applicant): Druggable regulators of nitric oxide production as new Alzheimer's disease therapeutics Summary: Nitrosative stress is a critical mediator of the onset and progression of Alzheimer's disease (AD): it precedes and is associated with neuritic dystrophy and dendritic spine loss, A /amyloid accumulation and deposition, cholinergic denervation and a memory loss phenotype in animal models of disease. Normally, nitric oxide (NO) is an important signaling molecule and the enzymethat produces it, nitric oxide synthase (NOS), regulates ApoE and its other protein partners via nitrosylation. Under pro-inflammatory conditions (e.g. AD), oxidative stress upregulates NOS. Excess NO combines with oxygen radicals forming the reactive nitrosylating species peroxynitrite, which in turn causes promiscuous dysregulation and indiscriminate damage. Because direct inhibition of NOS results in systemic toxicity, our unique strategy is to selectively reduce NO activity at sites of inflammation. This will be achieved by targeting Sigma- 1 receptors (S1R), because they become important regulators of NOS activity only under conditions of oxidative stress. Our hypothesis is that elevated brain NO levels can be lowered at inflammatory sites by drugs that promote S1R-mediated reductions in NOS activity. The path for discovery and proof-of-concept phases includes: A) synthesis of additional novel candidate molecules to impart the appropriate selectivity and drug-like characteristics to compounds that reduce NO levels and promote neuronal and/or glial cell survival in vitro under conditions of nitrosative stress; B) evaluate 1- of these leads in a transgenic mouse model of AD by measuring reductions in CNS A /amyloid burden, 3-nitrotyrosine levels and improvements in cognition. Novel high affinity S1R candidates (hits) have been identified in our preliminary work and now we seek to create leads with refined drug-like properties for testing our target and mechanism- based hypothesis for therapeutics designed to slow the progression of AD. PUBLIC HEALTH RELEVANCE: The objective is to discover and develop news drugs for the treatment of Alzheimer's disease, a leading cause of morbidity and mortality in the US.

* information listed above is at the time of submission.

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