Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 10, Pages 4593-4607Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00389
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Funding
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2013-00017-C]
- New Investigator Award from the American Association of Colleges of Pharmacy (AACP)
- Alzheimer's Association [NIRG-15-363739]
- National Institutes of Health [R01AG057598]
- Office of Undergraduate Research at the University of Toledo
- National Science Foundation [1432921]
- Direct For Education and Human Resources
- Division Of Human Resource Development [1432921] Funding Source: National Science Foundation
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Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer's disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the central nervous system. Furoxan Sa demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP-dependent neuroprotection was observed, and 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, Sa can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 h after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.
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