Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors.

ABSTRACT: 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 IC₅₀ values <5 nmol/L. In addition, these four compounds showed low cell toxicity in human SH-SY5Y neuroblastoma cells. Compound 11a, the most effective one, gave the IC₅₀ of 1.1 nmol/L towards PDE9, which is significantly better than the reference compounds PF-04447943 and BAY 73-6691. The ana

SUBMITTER: Wu XN 

PROVIDER: S-EPMC6089849 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature