Discovery of Potent, Selective, and Orally Bioavailable Inhibitors against Phosphodiesterase-9, a Novel Target for the Treatment of Vascular Dementia

To
identify phosphodiesterase-9 (PDE9) as a novel target for the
treatment of vascular dementia (VaD), a series of pyrazolo­pyrimidinone
analogues were discovered based on a hit 1. Hit-to-lead
optimization resulted in a potent inhibitor 2 with excellent
selectivity and physicochemical properties to enable in vivo studies.
Oral administration of 2 (5.0 mg/kg) caused notable therapeutic
effects in the VaD mouse model, providing a promising lead or chemical
probe for investigating the biological functions of PDE9 inhibition.