ArticleNature biotechnology2010
Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Article in Nature biotechnology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 147 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
147 citing papers in PubMed, 392 citations in OpenAlex.
- Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.Nature medicine · 2021Trial
- Peel of Pomegranate Fruit (Current issues in molecular biology · 2026Article
- Trends in Inhibitors, Structural Modifications, and Structure-Function Relationships of Phosphodiesterase 4: A Review.Biomolecules · 2026Review
- Combining Experimental Assays and Molecular Modeling to Evaluate Monosubstituted Cinnamic Acid Derivatives as PDE4B Inhibitors.ACS omega · 2025Article
- Posttranslational modifications of phosphodiesterase type 4 enzymes represent novel points for therapeutic targeting.The FEBS journal · 2025Review
- Cinobufagin Directly Targets PDE4D to Disrupt Fibroblast-Dendritic Cell Crosstalk in Atopic Dermatitis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Molecular Mechanism of PDE1 Regulation.Cells · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Review
- Molecular Properties of Phosphodiesterase 4 and Its Inhibition by Roflumilast and Cilomilast.Molecules (Basel, Switzerland) · 2025Review
- Pharmacological characterization and preclinical evaluation of 11h: a novel, brain-penetrant PDE4 inhibitor for neurological disorders.Frontiers in pharmacology · 2025Article
- 3D-QSAR Studies on High-affinity Phosphodiestera.Current medicinal chemistry · 2025Article
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- PDE4D: A Multipurpose Pharmacological Target.International journal of molecular sciences · 2024Review
- Therapeutic perspectives on PDE4B inhibition in adipose tissue dysfunction and chronic liver injury.Expert opinion on therapeutic targets · 2024Review
- Targeting Aquaporin-5 by Phosphodiesterase 4 Inhibition Offers New Therapeutic Opportunities for Ovarian Ischemia Reperfusion Injury in Rats.Reproductive sciences (Thousand Oaks, Calif.) · 2024Article
- Robust Quantification of Phosphodiesterase-4D in Monkey Brain with PET andJournal of nuclear medicine : official publication, Society of Nuclear Medicine · 2024Article
- Allosteric inhibition of phosphodiesterase 4D induces biphasic memory-enhancing effects associated with learning-activated signaling pathways.Psychopharmacology · 2024Article
- Topical Application of Dipyridamole and Roflumilast Combination Nanoparticles Loaded Nanoemulgel for the Treatment of Psoriasis in Rats.International journal of nanomedicine · 2024Article
- PDE4 Inhibitors and their Potential Combinations for the Treatment of Chronic Obstructive Pulmonary Disease: A Narrative Review.The open respiratory medicine journal · 2024Review
87 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
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What OpenQuestion holds
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.