ArticleCellular signalling2014
Structural basis for the design of selective phosphodiesterase 4B inhibitors.
Article in Cellular signalling, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 102 citations in OpenAlex.
- PDE4 inhibitor rolipram dynamically regulates the balance between D1-MSNs and D2-MSNs in the DMS to modulate abnormal "Go" behavior associated with alcohol addiction.Acta pharmacologica Sinica · 2026Article
- Phosphodiesterase 4B (PDE4B) inhibitors and their applications in recent years (2014 to early 2025).Molecular diversity · 2026Review
- Trends in Inhibitors, Structural Modifications, and Structure-Function Relationships of Phosphodiesterase 4: A Review.Biomolecules · 2026Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Inhibition of PDE4B ameliorates cognitive defects in the model of alcoholic dementia in 3xTg-AD mice via PDE4B/cAMP/PKA signaling.The international journal of neuropsychopharmacology · 2025Article
- Review
- Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.Expert opinion on therapeutic targets · 2024Review
- Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice.Cells · 2024Article
- PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review.The open respiratory medicine journal · 2024Review
- Anti-Neurodegenerating Activity: Structure-Activity Relationship Analysis of Flavonoids.Molecules (Basel, Switzerland) · 2023Article
- Selective PDE4B and PDE4D inhibitors produce distinct behavioral responses to ethanol and GABAergic drugs in mice.Neuropharmacology · 2023Article
- An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands.Journal of medicinal chemistry · 2023Article
- Apremilast-induced increases in acute ethanol intoxication and decreases in ethanol drinking in mice involve PKA phosphorylation of GABANeuropharmacology · 2022Article
- Selective Inhibition of PDE4B Reduces Methamphetamine Reinforcement in Two C57BL/6 Substrains.International journal of molecular sciences · 2022Article
- Selective Inhibition of PDE4B Reduces Binge Drinking in Two C57BL/6 Substrains.International journal of molecular sciences · 2021Article
- PDE4B Induces Epithelial-to-Mesenchymal Transition in Bladder Cancer Cells and Is Transcriptionally Suppressed by CBX7.Frontiers in cell and developmental biology · 2021Article
- Phosphodiesterase-4 Inhibitors for Non-COPD Respiratory Diseases.Frontiers in pharmacology · 2021Review
- Docking based screening and molecular dynamics simulations to identify potential selective PDE4B inhibitor.Heliyon · 2020Article
- Review
- PDE4 subtypes in cancer.Oncogene · 2020Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Phosphodiesterase-4B (PDE4B) regulates the pro-inflammatory Toll Receptor -Tumor Necrosis Factor α (TNFα) pathway in monocytes, macrophages and microglial cells. As such, it is an important, although under-exploited molecular target for anti-inflammatory drugs. This is due in part to the difficulty of developing selective PDE4B inhibitors as the amino acid sequence of the PDE4 active site is identical in all PDE4 subtypes (PDE4A-D). We show that highly selective PDE4B inhibitors can be designed by exploiting sequence differences outside the active site. Specifically, PDE4B selectivity can be achieved by capture of a C-terminal regulatory helix, now termed CR3 (Control Region 3), across the active site in a conformation that closes access by cAMP. PDE4B selectivity is driven by a single amino acid polymorphism in CR3 (Leu674 in PDE4B1 versus Gln594 in PDE4D). The reciprocal mutations in PDE4B and PDE4D cause a 70-80 fold shift in selectivity. Our structural studies show that CR3 is flexible and can adopt multiple orientations and multiple registries in the closed conformation. The new co-crystal structure with bound ligand provides a guide map for the design of PDE4B selective anti-inflammatory drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.