Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases

Reeves, Erica K.M.; Rayavarapu, Sree; Damsker, Jesse M.; Nagaraju, Kanneboyina

doi:10.2174/187153012799279045

Cited by 17 publications

(11 citation statements)

References 64 publications

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“…For example, in Duchenne muscular dystrophy, daily prednisone is considered standard of care in some countries, but the efficacy if offset by increased bone fragility, mood changes, weight gain, and muscle catabolic pathways. 23–26 Thus, there is non-adoption of this standard in some countries, and relatively poor adherence even in those countries adopting daily glucocorticoids. 27 The VBP15 described here is being developed for Duchenne muscular dystrophy as the initial indication, in collaboration with the Muscular Dystrophy Association Venture Philanthropy, and National Institutes of Health Therapeutics for Rare and Neglected Disease program.…”

Section: Discussionmentioning

confidence: 99%

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Reeves

Hoffman

Nagaraju

et al. 2013

Bioorganic & Medicinal Chemistry

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Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus. We concluded that Δ9,11 steroids showed novel anti-inflammatory properties, retaining NF-κB inhibition, but losing deleterious glucocorticoid side effect profiles. Evidence for this was developed in pre-clinical trials of chronic muscle inflammation. Here, we describe a drug development program aimed at optimizing the Δ9,11 chemistry. Twenty Δ9,11 derivatives were tested in in vitro screens for NF-κB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-κB inhibition and GR translocation similar to prednisone and dexamethasone, lack of transactivation properties, and good bioavailability. Phamacokinetics were similar to traditional glucocorticoid drugs with terminal half-life of 0.35 h (mice), 0.58 h (rats), 5.42 h (dogs), and bioavailability of 74.5% (mice), and 53.2% (dogs). Metabolic stability showed ≥80% remaining at 1 h of VBP6 and VBP15 in human, dog, and monkey liver microsomes. Solubility, permeability and plasma protein binding were within acceptable limits. VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24–42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy.

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Section: Discussionmentioning

confidence: 99%

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Reeves

Hoffman

Nagaraju

et al. 2013

Bioorganic & Medicinal Chemistry

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“…Their beneficial effects are mostly ascribed to reduced inflammation [46]. However, adverse effects must be considered: weight gain, growth retardation, and cushingoid appearance are described as well as fractures, hypertension, and glucose intolerance [47, 48].…”

Section: Discussionmentioning

confidence: 99%

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

Lecompte

Abou‐Samra

Boursereau

et al. 2017

Cell. Mol. Life Sci.

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BackgroundPersistent inflammation exacerbates the progression of Duchenne muscular dystrophy (DMD). The hormone, adiponectin (ApN), which is decreased in the metabolic syndrome, exhibits anti-inflammatory properties on skeletal muscle and alleviates the dystrophic phenotype of mdx mice. Here, we investigate whether ApN retains its anti-inflammatory action in myotubes obtained from DMD patients. We unravel the underlying mechanisms by studying the secretome and the early events of ApN.MethodsPrimary cultures of myotubes from DMD and control patients were treated or not by ApN after an inflammatory challenge. Myokines secreted in medium were identified by cytokine antibody-arrays and ELISAs. The early events of ApN signaling were assessed by abrogating selected genes.ResultsApN retained its anti-inflammatory properties in both dystrophic and control myotubes. Profiling of secretory products revealed that ApN downregulated the secretion of two pro-inflammatory factors (TNFα and IL-17A), one soluble receptor (sTNFRII), and one chemokine (CCL28) in DMD myotubes, while upregulating IL-6 that exerts some anti-inflammatory effects. These changes were explained by pretranslational mechanisms. Earlier events of the ApN cascade involved AdipoR1, the main receptor for muscle, and the AMPK-SIRT1-PGC-1α axis leading, besides alteration of the myokine profile, to the upregulation of utrophin A (a dystrophin analog).ConclusionApN retains its beneficial properties in dystrophic muscles by activating the AdipoR1-AMPK-SIRT1-PGC-1α pathway, thereby inducing a shift in the secretion of downstream myokines toward a less inflammatory profile while upregulating utrophin. ApN, the early events of the cascade and downstream myokines may be therapeutic targets for the management of DMD.

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“…AL-438 was even able to prevent GC-induced hyperglycemia (Coghlan et al, 2003). Research on the effect of LGD-5552 on glucose housekeeping still needs to be performed (Reeves et al, 2012).…”

Section: Side Effectsmentioning

confidence: 99%

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

Sundahl

Bridelance

Libert

et al. 2015

Pharmacology & Therapeutics

186

171

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Glucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions. We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies.

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Glucocorticoid Analogues: Potential Therapeutic Alternatives for Treating Inflammatory Muscle Diseases

Cited by 17 publications

References 64 publications

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Skeletal muscle secretome in Duchenne muscular dystrophy: a pivotal anti-inflammatory role of adiponectin

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

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