Detalle Publicación


Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer's Disease

Autores: Sanchez-Arias, J. A.; Rabal Gracia, María Obdulia; Cuadrado Tejedor, María del Mar; de Miguel, I.; Perez-Gonzalez, M.; Ugarte, A.; Sáez de Blas, Elena; Espelosin, M.; Ursua, S.; Haizhong, T.; Wei, W.; Musheng, X.; García Osta, Ana María; Oyarzabal Santamarina, Julen
ISSN: 1948-7193
Volumen: 15
Número: 8
Páginas: 638 - 661
Fecha de publicación: 2017
Sánchez-Arias J.A.; María Obdulia Rabal Gracia; María del Mar Cuadrado Tejedor; Ana María García Osta and Julen Oyarzábal Santamarina, contributed equally to this work. 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.