title: Discovery of novel PDE9 inhibitors capable of inhibiting Aβ aggregation as potential candidates for the treatment of Alzheimer's disease.
abstract: Recently, phosphodiesterase-9 (PDE9) inhibitors and biometal-chelators have received much attention as potential therapeutics for the treatment of Alzheimer's disease (AD). Here, we designed, synthesized, and evaluated a novel series of PDE9 inhibitors with the ability to chelate metal ions. The bioassay results showed that most of these molecules strongly inhibited PDE9 activity. Compound 16 showed an IC50 of 34 nM against PDE9 and more than 55-fold selectivity against other PDEs. In addition, this compound displayed remarkable metal-chelating capacity and a considerable ability to halt copper redox cycling. Notably, in comparison to the reference compound clioquinol, it inhibited metal-induced Aβ(1-42) aggregation more effectively and promoted greater disassembly of the highly structured Aβ fibrils generated through Cu(2+)-induced Aβ aggregation. These activities of 16, together with its favorable blood-brain barrier permeability, suggest that 16 may be a promising compound for treatment of AD.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Su
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Tianhua
authors.initials: T
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Shishun
authors.initials: S
authors.lastname: Xie
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Wu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xingshu
authors.initials: X
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D007464:Clioquinol / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000737:chemistry; D006801:Humans; D046529:Microscopy, Electron, Transmission; D062105:Molecular Docking Simulation; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011744:Pyrimidinones / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C000613051:(R)-1-cyclopentyl-6-(1-((2-hydroxy-4-methoxybenzyl)amino)ethyl)-1H-pyrazolo(3,4-d)pyrimidin-4(5H)-one; D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; C075222:amyloid beta-protein (1-42); D003300:Copper; D007464:Clioquinol; D015105:3',5'-Cyclic-AMP Phosphodiesterases