Furoxans (Oxadiazole-4 N-oxides) with Attenuated Reactivity are Neuroprotective, Cross the Blood Brain Barrier, and Improve Passive Avoidance Memory.
J Med Chem
; 61(10): 4593-4607, 2018 05 24.
Article
em En
| MEDLINE
| ID: mdl-29683322
ABSTRACT
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 5a 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, 5a 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.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Oxidiazóis
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Aprendizagem da Esquiva
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Barreira Hematoencefálica
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Fármacos Neuroprotetores
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Neuroproteção
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Transtornos da Memória
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article