Selective Glucocorticoid Receptor Agonists for the Treatment of Inflammatory Bowel Disease: Studies in Mice with Acute Trinitrobenzene Sulfonic Acid Colitis

Reuter, Kerstin C.; Grunwitz, Christian; Kaminski, Bettina Maria; Steinhilber, Dieter; Radeke, Heinfried H.; Stein, Jürgen M.

doi:10.1124/jpet.111.183947

Cited by 40 publications

(39 citation statements)

References 41 publications

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“…Our results show that CpdA moderately ameliorated signs of arthritis, including the disease activity score and the T cell response, but to a weaker extent as DEX. This is in line with previous findings indicating that CpdA diminishes parameters of the Th1 immune response and reduces inflammation (26,27). However, it should be noted that DEX was more efficient in suppressing inflammation as evident by the lower paw temperature and the smaller extent of cellular infiltrates in the synovium and cartilage damage.…”

Section: Discussionsupporting

confidence: 80%

“…However, our data suggest that CpdA exerted adverse effects on the gastrointestinal (GI) tract and that those effects may depend on an increased rate of apoptosis in the colonic tissue (data not shown). Similar side effects were reported by Reuter et al (26), who also showed an increased apoptosis rate in colonic tissue after CpdA treatment. In contrast to CpdA, the second tested SEGRA in that study, ZK216348, did not reveal apoptosis-inducing effects, indicating that this is a CpdA-specific trait (26).…”

Section: Discussionsupporting

confidence: 73%

“…Similar side effects were reported by Reuter et al (26), who also showed an increased apoptosis rate in colonic tissue after CpdA treatment. In contrast to CpdA, the second tested SEGRA in that study, ZK216348, did not reveal apoptosis-inducing effects, indicating that this is a CpdA-specific trait (26). One possible explanation for the proapoptotic effects of CpdA in vivo is the fact that CpdA is an aziridine precursor and can degrade into aziridines at physiological pH (19,29).…”

Section: Discussionsupporting

confidence: 73%

“…One possible explanation for the proapoptotic effects of CpdA in vivo is the fact that CpdA is an aziridine precursor and can degrade into aziridines at physiological pH (19,29). These alkylating reagents are highly reactive and may account for the toxic effects of CpdA at higher dosages (26,30). In light of the toxicity of CpdA, we were unable to use higher concentrations of CpdA that might have been more potent in reducing inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…These findings are further corroborated by our dose-finding experiments showing that a lower dose of CpdA does not suppress inflammation, whereas higher doses were toxic. The narrow therapeutic range of CpdA reflects a major limitation for its preclinical and clinical potential as reported (19,26).…”

Section: Discussionmentioning

confidence: 99%

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Effects of the Selective Glucocorticoid Receptor Modulator Compound A on Bone Metabolism and Inflammation in Male Mice With Collagen-Induced Arthritis

et al. 2013

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Glucocorticoids (GCs) are potent drugs to treat rheumatoid arthritis but exert adverse skeletal effects. Compound A (CpdA) is a selective GC receptor modulator with an improved risk/benefit profile in mouse models of inflammation and bone loss. Here we tested whether CpdA also exerts bone-sparing effects under proinflammatory circumstances using the collagen-induced arthritis model, a murine model of rheumatoid arthritis. CpdA decreased disease activity, paw swelling, and the paw temperature by 43%, 12%, and 7%, respectively, but was less potent than dexamethasone (DEX), which reduced these parameters by 72%, 22%, and 10%, respectively. Moreover, T cells isolated from CpdA-and DEX-treated animals were less active based on proliferation rates after challenge with type II collagen and produced smaller amounts of interferon-␥ and TNF as compared with T cells from PBS-treated mice. Histological assessment of the joints confirmed the weaker potency of CpdA as compared with DEX in preventing infiltration of inflammatory cells, induction of osteoclastogenesis, and destruction of articular cartilage. Due to the lack of GC-susceptible arthritis models, we were not able to fully address the bone-sparing potential of CpdA in inflammatory conditions. Nevertheless, the bone formation marker procollagen type 1 N-terminal peptide, a surrogate marker for GC-mediated suppression of bone formation, was significantly decreased by DEX in arthritic mice but not by CpdA. Our data indicate that CpdA moderately suppresses inflammation, whereas the concurrent effects on bone remain unknown. In light of its narrow therapeutic range, CpdA may be more useful as a molecular tool for dissecting GC actions rather than a therapeutic agent. (Endocrinology 154: 3719 -3728, 2013)

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Section: Discussionsupporting

confidence: 80%

Section: Discussionsupporting

confidence: 73%

Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of the Selective Glucocorticoid Receptor Modulator Compound A on Bone Metabolism and Inflammation in Male Mice With Collagen-Induced Arthritis

et al. 2013

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Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Pang

Zhang

et al. 2021

Advanced Science

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Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators.

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Construction of Polyheterocyclic Compounds by Lewis Acid Mediated Intramolecular [3+2] Cycloaddition Reaction

et al. 2023

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An efficient domino approach has been developed for the synthesis of polyheterocyclic derivatives constituting pyrrole moiety. Lewis acid catalyzed reaction of 2‐substituted‐2‐hydroxy‐indane‐1,3‐diones and 1,4‐benzoxazinone derivatives resulted in the formation of polyheterocyclic compounds under metal‐free and mild conditions in good to excellent yield. The reaction is highly regioselective for C−C and C−N bond construction proceeded via intramolecular [3+2] cycloaddition reaction. The protocol is highly efficient, obviates column chromatography and the products are obtained by simple filtration followed by washing with solvent.

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Selective Glucocorticoid Receptor Agonists for the Treatment of Inflammatory Bowel Disease: Studies in Mice with Acute Trinitrobenzene Sulfonic Acid Colitis

Cited by 40 publications

References 41 publications

Effects of the Selective Glucocorticoid Receptor Modulator Compound A on Bone Metabolism and Inflammation in Male Mice With Collagen-Induced Arthritis

Effects of the Selective Glucocorticoid Receptor Modulator Compound A on Bone Metabolism and Inflammation in Male Mice With Collagen-Induced Arthritis

Discovery of Novel GR Ligands toward Druggable GR Antagonist Conformations Identified by MD Simulations and Markov State Model Analysis

Construction of Polyheterocyclic Compounds by Lewis Acid Mediated Intramolecular [3+2] Cycloaddition Reaction

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