ACS Chemical Neuroscience p. 638 - 661 (2017)
Update date:2022-08-15
Topics:
Sánchez-Arias, Juan A.
Rabal, Obdulia
Cuadrado-Tejedor, Mar
De Miguel, Irene
Pérez-González, Marta
Ugarte, Ana
Sáez, Elena
Espelosin, Maria
Ursua, Susana
Haizhong, Tan
Wei, Wu
Musheng, Xu
Garcia-Osta, Ana
Oyarzabal, Julen
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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