Design, Synthesis, and Biological Evaluation of First-in-Class Dual Acting Histone Deacetylases (HDACs) and Phosphodiesterase 5 (PDE5) Inhibitors for the Treatment of Alzheimer’s Disease

Simultaneous
inhibition of phosphodiesterase 5 (PDE5) and histone deacetylases
(HDAC) has recently been validated as a potentially novel therapeutic
approach for Alzheimer’s disease (AD). To further extend this
concept, we designed and synthesized the first chemical series of
dual acting PDE5 and HDAC inhibitors, and we validated this systems
therapeutics approach. Following the implementation of structure-
and knowledge-based approaches, initial hits were designed and were
shown to validate our hypothesis of dual in vitro inhibition. Then, an optimization strategy was pursued to obtain
a proper tool compound for in vivo testing in AD
models. Initial hits were translated into molecules with adequate
cellular functional responses (histone acetylation and cAMP/cGMP response
element-binding (CREB) phosphorylation in the nanomolar range), an
acceptable therapeutic window (>1 log unit), and the ability to
cross the blood–brain barrier, leading to the identification
of 7 as a candidate for in vivo proof-of-concept
testing (Cuadrado-Tejedor, M.; Garcia-Barroso,
C.; Sánchez-Arias, J. A.; Rabal, O.; Mederos, S.; Ugarte, A.;
Franco, R.; Segura, V.; Perea, G.; Oyarzabal, J.; Garcia-Osta, A. Neuropsychopharmacology 2016, in press,
doi: 10.1038/npp.2016.163).