Multitarget Approach for the Treatment of Alzheimer’s Disease: Inhibition of Phosphodiesterase 9 (PDE9) and Histone Deacetylases (HDACs) Covering Diverse Selectivity Profiles

Here,
we present a series of dual-target phosphodiesterase 9 (PDE9)
and histone deacetylase (HDAC) inhibitors devised as pharmacological
tool compounds for assessing the implications of these two targets
in Alzheimer’s disease (AD). These novel inhibitors were designed
taking into account the key pharmacophoric features of known selective
PDE9 inhibitors as well as privileged chemical structures, bearing
zinc binding groups (hydroxamic acids and ortho-amino
anilides) that hit HDAC targets. These substituents were selected
according to rational criteria and previous knowledge from our group
to explore diverse HDAC selectivity profiles (pan-HDAC, HDAC6 selective,
and class I selective) that were confirmed in biochemical screens.
Their functional response in inducing acetylation of histone and tubulin
and phosphorylation of cAMP response element binding (CREB) was measured
as a requisite for further progression into complete in vitro absorption, distribution, metabolism and excretion (ADME) and in vivo brain penetration profiling. Compound 31b, a selective HDAC6 inhibitor with acceptable brain permeability,
was chosen for assessing in vivo efficacy of these
first-in-class inhibitors, as well as studying their mode of action
(MoA).