Discovery of in-vivo chemical probes for treating Alzheimer´s disease: Dual phosphodiesterase 5 (PDE5) and class I histone deacetylases-selective inhibitors.

In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual 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 phosphodiesterase 5 (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 pre-incubation 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).