The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable prec...The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC_(50) values 5n mol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells.Compound 11a, the most effective one, gave the IC_(50) of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure–activity relationships and provide evidence for further structural modifications.展开更多
基金supported by the National Key R&D Program of China (2017YFB0202600)Natural Science Foundation of China (Nos. 81522041,81373258,21572279,81602955,and 21402243)+3 种基金Science Foundation of Guangdong Province (Nos. 2014A020210009,2016A030310144)The Fundamental Research Funds for the Central Universities (Sun Yat-Sen University,No. 17ykjc03 and 17ykpy20)Guangdong Province Higher Vocational Colleges & Schools Pearl River Scholar Funded Scheme (2016)Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund (the second phase) under Grant No. U1501501 for providing the supercomputing service
文摘The pathological processes of Alzheimer's disease and type 2 diabetes mellitus have been demonstrated to be linked together. Both PDE9 inhibitors and PPARγ agonists such as rosiglitazone exhibited remarkable preclinical and clinical treatment effects for these two diseases. In this study, a series of PDE9 inhibitors combining the pharmacophore of rosiglitazone were discovered. All the compounds possessed remarkable affinities towards PDE9 and four of them have the IC_(50) values 5n mol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells.Compound 11a, the most effective one, gave the IC_(50) of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The analysis of putative binding patterns and binding free energy of the designed compounds with PDE9 may explain the structure–activity relationships and provide evidence for further structural modifications.
