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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


Year of Publication:
Contact PI Name:
Julen Oyarzabal
Contact PI Affiliation:
Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
Mar Cuadrado-Tejedor, Carolina Garcia-Barroso, Juan A Sánchez-Arias3, Obdulia Rabal, Marta Pérez-González, Sara Mederos, Ana Ugarte, Rafael Franco, Victor Segura, Gertrudis Perea, Ana Garcia-Osta
Primary Reference (PubMED ID):
Funding Source:
UTE project FIMA
Torres Quevedo
Asociación de Amigos of University of Navarra
Spanish Ministry of Economy and Competitiveness (MINECO)
Fondo de Investigacion Sanitaria (FIS)/Fund for the Health of Spain
Study Goal and Principal Findings:

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). This study reports the discovery of a new first-in-class small-molecule (CM-414) that acts as a dual inhibitor of PDE5 and HDACs. They 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Histone Deacetylases
Therapeutic Target:
Phosphodiesterase Type 5A (PDE5A)

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported
Animal Model Notes:
The authors do not specify which APPswe/PSEN1dE9 model is used in this study.

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Fear Conditioning Response
Morris Water Maze
Histone Deacetylase (HDAC) Activity
Phosphodiesterase 5 (PDE5) Activity
Matrix Metalloproteinase 3 (MMP3) Activity
Matrix Metalloproteinase 10 (MMP10) Activity
Aggregated Tau
Amyloid Precursor Protein (APP)
APP-CTF99 (CTF beta)
Acetyl-Histone H3 Lysine 9 (H3K9ac)
Brain-beta Amyloid Peptide 42
phospho-Glutamate Ionotropic Receptor NMDA Type Subunit 2A (phospho-GluN2A/NR2A)
Glutamate Ionotropic Receptor AMPA Type Subunit 2/3 (GluR2/3)
Glutamate Ionotropic Receptor NMDA Type Subunit 2B (GluN2B/NR2B)
Postsynaptic Density Protein 95 (PSD95)
Ephrin Type B Receptor 2 (EPHB2)
Glycogen Synthase Kinase 3 beta (GSK3 beta)
phospho-Extracellular Signal-Regulated Kinase 1/2 (phospho-ERK1/2)
phospho-Glutamate Ionotropic Receptor AMPA Type Subunit 1 (phospho-GluR1)
phospho-Glycogen Synthase Kinase 3 beta (phospho-GSK3 beta)
Dendritic Spine Density
Synaptic Transmission Strength
Drug Concentration-Plasma
Micro Array Expression Analysis