Discovery of novel phosphodiesterase-1 inhibitors for curing vascular dementia: Suppression of neuroinflammation by blocking NF-B transcription regulation and activating cAMP/CREB axis.

Vascular dementia (VaD) is the second commonest type of dementia which lacks of efficient treatments currently. Neuroinflammation as a prominent pathological feature of VaD, is highly involved in the development of VaD. In order to verify the therapeutic potential of PDE1 inhibitors against VaD, the anti-neuroinflammation, memory and cognitive improvement were evaluated and by a potent and selective PDE1 inhibitor . Also, the mechanism of in ameliorating neuroinflammation and VaD was systematically explored. Furthermore, to optimize the drug-like properties of , especially for metabolic stability, 15 derivatives were designed and synthesized. As a result, candidate , with a potent IC value of 4.5 nmol/L against PDE1C, high selectivity over PDEs, and remarkable metabolic stability, efficiently ameliorated neuron degeneration, cognition and memory impairment in VaD mice model by suppressing NF-B transcription regulation and activating cAMP/CREB axis. These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.