ACS Chemical Neuroscience p. 1765 - 1782 (2019)
Update date:2022-08-15
Topics:
Rabal, Obdulia
Sánchez-Arias, Juan A.
Cuadrado-Tejedor, Mar
De Miguel, Irene
Pérez-González, Marta
García-Barroso, Carolina
Ugarte, Ana
Estella-Hermoso De Mendoza, Ander
Sáez, Elena
Espelosin, Maria
Ursua, Susana
Haizhong, Tan
Wei, Wu
Musheng, Xu
Garcia-Osta, Ana
Oyarzabal, Julen
In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
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