ArticleNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2017
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.
Article in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 103 citations in OpenAlex.
- Histone Deacetylases in Neurodegenerative Diseases and Their Potential Role as Therapeutic Targets: Shedding Light on Astrocytes.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Review
- Recent Insights into the Creation of Histone Deacetylase Inhibitors for the Treatment of Human Diseases.International journal of molecular sciences · 2025Review
- Sleep patterns, plasma metabolites, and risk of incident osteoarthritis: a prospective cohort study.Scientific reports · 2025Article
- Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases.Current topics in medicinal chemistry · 2025Review
- The broken Alzheimer's disease genome.Cell genomics · 2024Review
- Unlocking the epigenetic symphony: histone acetylation's impact on neurobehavioral change in neurodegenerative disorders.Epigenomics · 2024Review
- Advancements in Phosphodiesterase 5 Inhibitors: Unveiling Present and Future Perspectives.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Enhancement of neural regeneration as a therapeutic strategy for Alzheimer's disease (Review).Experimental and therapeutic medicine · 2023Review
- Small molecule modulators of chromatin remodeling: from neurodevelopment to neurodegeneration.Cell & bioscience · 2023Review
- Novel 9-Benzylaminoacridine Derivatives as Dual Inhibitors of Phosphodiesterase 5 and Topoisomerase II for the Treatment of Colon Cancer.Molecules (Basel, Switzerland) · 2023Article
- Male histone deacetylase 6 (HDAC6) knockout mice have enhanced ventilatory responses to hypoxic challenge.Frontiers in physiology · 2023Article
- [Nature communications · 2022Article
- ROCK and PDE-5 Inhibitors for the Treatment of Dementia: Literature Review and Meta-Analysis.Biomedicines · 2022Review
- Age-dependent attenuation of spatial memory deficits by the histone acetyltransferase p300/CBP-associated factor (PCAF) in 3xTG Alzheimer's disease mice.Learning & memory (Cold Spring Harbor, N.Y.) · 2022Article
- Inhibition of phosphodiesterase: A novel therapeutic target for the treatment of mild cognitive impairment and Alzheimer's disease.Frontiers in aging neuroscience · 2022Review
- Advances in Genetics and Epigenetic Alterations in Alzheimer's Disease: A Notion for Therapeutic Treatment.Genes · 2021Review
- Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue.Pharmaceuticals (Basel, Switzerland) · 2021Review
- HDAC inhibition ameliorates cone survival in retinitis pigmentosa mice.Cell death and differentiation · 2021Article
- Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6.RSC medicinal chemistry · 2021Review
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Registered trials
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