ArticleThe Journal of pharmacology and experimental therapeutics2012
Δ-9,11 modification of glucocorticoids dissociates nuclear factor-κB inhibitory efficacy from glucocorticoid response element-associated side effects.
Article in The Journal of pharmacology and experimental therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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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.
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Who cites it
16 citing papers in PubMed, 30 citations in OpenAlex.
- Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug.Pharmacological research · 2018Trial
- Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial.Orphanet journal of rare diseases · 2013Trial
- Structure-property Relationships Reported for the New Drugs Approved in 2023.Mini reviews in medicinal chemistry · 2024Review
- Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies.Biomolecules · 2023Review
- Considering the Promise of Vamorolone for Treating Duchenne Muscular Dystrophy.Journal of neuromuscular diseases · 2023Article
- Current Strategies of Muscular Dystrophy Therapeutics: An Overview.Methods in molecular biology (Clifton, N.J.) · 2023Review
- Corticosteroid Treatment-Resistance in Myasthenia Gravis.Frontiers in neurology · 2022Review
- Therapeutic developments for Duchenne muscular dystrophy.Nature reviews. Neurology · 2019Review
- Membrane Stabilization by Modified Steroid Offers a Potential Therapy for Muscular Dystrophy Due to Dysferlin Deficit.Molecular therapy : the journal of the American Society of Gene Therapy · 2018Article
- The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice.Scientific reports · 2018Article
- Immunogenomics reveal molecular circuits of diclofenac induced liver injury in mice.Oncotarget · 2016Article
- Pharmacologically-induced mitotic synchrony in airway epithelial cells as a mechanism of action of anti-inflammatory drugs.Respiratory research · 2015Article
- VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects.EMBO molecular medicine · 2013Article
- VBP15: preclinical characterization of a novel anti-inflammatory delta 9,11 steroid.Bioorganic & medicinal chemistry · 2013Article
- VBP15, a glucocorticoid analogue, is effective at reducing allergic lung inflammation in mice.PloS one · 2013Article
- Novel approaches to corticosteroid treatment in Duchenne muscular dystrophy.Physical medicine and rehabilitation clinics of North America · 2012Review
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Glucocorticoids are standard of care for many inflammatory conditions, but chronic use is associated with a broad array of side effects. This has led to a search for dissociative glucocorticoids--drugs able to retain or improve efficacy associated with transrepression [nuclear factor-κB (NF-κB) inhibition] but with the loss of side effects associated with transactivation (receptor-mediated transcriptional activation through glucocorticoid response element gene promoter elements). We investigated a glucocorticoid derivative with a Δ-9,11 modification as a dissociative steroid. The Δ-9,11 analog showed potent inhibition of tumor necrosis factor-α-induced NF-κB signaling in cell reporter assays, and this transrepression activity was blocked by 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU-486), showing the requirement for the glucocorticoid receptor (GR). The Δ-9,11 analog induced the nuclear translocation of GR but showed the loss of transactivation as assayed by GR-luciferase constructs as well as mRNA profiles of treated cells. The Δ-9,11 analog was tested for efficacy and side effects in two mouse models of muscular dystrophy: mdx (dystrophin deficiency), and SJL (dysferlin deficiency). Daily oral delivery of the Δ-9,11 analog showed a reduction of muscle inflammation and improvements in multiple muscle function assays yet no reductions in body weight or spleen size, suggesting the loss of key side effects. Our data demonstrate that a Δ-9,11 analog dissociates the GR-mediated transcriptional activities from anti-inflammatory activities. Accordingly, Δ-9,11 analogs may hold promise as a source of safer therapeutic agents for chronic inflammatory disorders.
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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.