Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease.
ACS Chem Neurosci
; 8(3): 638-661, 2017 03 15.
Article
em En
| MEDLINE
| ID: mdl-27936591
ABSTRACT
A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer's disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.
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Base de dados:
MEDLINE
Assunto principal:
Inibidores de Histona Desacetilases
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Inibidores da Fosfodiesterase 5
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article