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...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 in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 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-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.展开更多
基金supported by the National Natural Science Foundation of China(22077143,21977127,and 21877134)Science Foundation of Guangzhou City(201904020023,China)+2 种基金Fundamental Research Funds for Hainan University(KYQD(ZR)-21031,China)Science of Guangdong Province(2019A1515011883,China)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China).
文摘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 in vitro and in vivo by a potent and selective PDE1 inhibitor 4a.Also,the mechanism of 4a in ameliorating neuroinflammation and VaD was systematically explored.Furthermore,to optimize the drug-like properties of 4a,especially for metabolic stability,15 derivatives were designed and synthesized.As a result,candidate 5f,with a potent IC50 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-κB transcription regulation and activating cAMP/CREB axis.These results further identified PDE1 inhibition could serve as a new therapeutic strategy for treatment of VaD.
