title: A First-in-Class Small-Molecule that Acts as a Dual Inhibitor of HDAC and PDE5 and that Rescues Hippocampal Synaptic Impairment in Alzheimer's Disease Mice.
abstract: The targeting of two independent but synergistic enzymatic activities, histone deacetylases (HDACs, class I and HDAC6) and phosphodiesterase 5 (PDE5), has recently been validated as a potentially novel therapeutic approach for Alzheimer's disease (AD). Here we report the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. We have used this compound as a chemical probe to validate this systems therapeutics strategy, where an increase in the activation of cAMP/cGMP-responsive element-binding protein (CREB) induced by PDE5 inhibition, combined with moderate HDAC class I inhibition, leads to efficient histone acetylation. This molecule rescued the impaired long-term potentiation evident in hippocampal slices from APP/PS1 mice. Chronic treatment of Tg2576 mice with CM-414 diminished brain Aβ and tau phosphorylation (pTau) levels, increased the inactive form of GSK3β, reverted the decrease in dendritic spine density on hippocampal neurons, and reversed their cognitive deficits, at least in part by inducing the expression of genes related to synaptic transmission. Thus, CM-414 may serve as the starting point to discover balanced dual inhibitors with an optimal efficacy and safety profile for clinical testing on AD patients.
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Cuadrado-Tejedor
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Garcia-Barroso
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Sánchez-Arias
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Obdulia
authors.initials: O
authors.lastname: Rabal
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-González
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Mederos
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Ugarte
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.|Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona, Barcelona, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Franco
authors.affiliation: Bioinformatics Unit, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.affiliation: Cajal Institute, CSIC, Madrid, Spain.
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Perea
authors.affiliation: Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.affiliation: Neurobiology of Alzheimer's Disease, Neurosciences Division, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Garcia-Osta
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects*; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D061251:Primary Cell Culture; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C000625799:CM-414; D056572:Histone Deacetylase Inhibitors; D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones