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

作　　者：Qian Zhou Meiling Le Yiyi Yang Wenjuan Wang Yuqi Huang Quan Wang Yijing Tian Meiyan Jiang Yong Rao Hai-Bin Luo Yinuo Wu 

机构地区：[1]School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [2]Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute,School of Pharmaceutical Sciences,Hainan University,Haikou 570228,China [3]Song Li’Academician Workstation of Hainan University(School of Pharmaceutical Sciences),Sanya 572000,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第3期1180-1191,共12页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(22077143,21977127,and 21877134);Science Foundation of Guangzhou City(201904020023,China);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).

摘　　要：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.

关 键 词：Vascular dementia Phosphodiesterase 1(PDE1) NEUROINFLAMMATION Structural-based drug design cAMP/CREB axis 

分 类 号：R749.13[医药卫生—神经病学与精神病学]