Characterization of ZK 245186, a novel, selective glucocorticoid receptor agonist for the topical treatment of inflammatory skin diseases

Abstract

Background and purpose: Glucocorticoids are highly effective in the therapy of inflammatory diseases. Their value, however, is limited by side effects. The discovery of the molecular mechanisms of the glucocorticoid receptor and the recognition that activation and repression of gene expression could be addressed separately opened the possibility of achieving improved safety profiles by the identification of ligands that predominantly induce repression. Here we report on ZK 245186, a novel, non-steroidal, low-molecular-weight, glucocorticoid receptor-selective agonist for the topical treatment of inflammatory dermatoses. Experimental approach: Pharmacological properties of ZK 245186 and reference compounds were studied in terms of their potential anti-inflammatory and side effects in functional bioassays in vitro and in rodent models in vivo. Key results: Anti-inflammatory activity of ZK 245186 was demonstrated in in vitro assays for inhibition of cytokine secretion and T cell proliferation. In vivo, using irritant contact dermatitis and T cell-mediated contact allergy models in mice and rats, ZK 245186 showed anti-inflammatory efficacy after topical application similar to the classical glucocorticoids, mometasone furoate and methylprednisolone aceponate. ZK 245186, however, exhibits a better safety profile with regard to growth inhibition and induction of skin atrophy after long-term topical application, thymocyte apoptosis, hyperglycaemia and hepatic tyrosine aminotransferase activity. Conclusions and implications: ZK 245186 is a potent anti-inflammatory compound with a lower potential for side effects, compared with classical glucocorticoids. It represents a promising drug candidate and is currently in clinical trials.

Anti-inflammatory Effects of Mapracorat, a Novel Selective Glucocorticoid Receptor Agonist, Is Partially Mediated by MAP Kinase Phosphatase-1 (MKP-1)

“…LPS (Escherichia coli, O55:B5) was purchased from EMD/Calbiochem and dissolved in PBS containing 0.1% BSA to a concentration of 10 mg/ml. (51) was synthesized by Bayer Schering Pharma (Berlin, Germany). Both dexamethasone (SigmaAldrich) and mapracorat were dissolved in DMSO (SigmaAldrich) to a concentration of 100 M. For the time course, cells were pretreated with 100 nM mapracorat for 4 h. Triptolide was acquired from Tocris Bioscience and prepared at a concentration of 10 mM DMSO.…”

Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex

“…It is now well accepted that tethered indirect transrepression accounts for many of the beneficial antiinflammatory effects of glucocorticoids, whereas (+)GRE-mediated transactivation and IR nGRE-mediated direct repression are responsible for most of the clinically debilitating effects (1,3). We report here that a compound (CpdX), which is related to a novel nonsteroidal antiinflammatory SEGRA named ZK245186 (19) or Mapracorat (18), cannot induce the transactivation and direct transrepression functions of the GR while still inducing its tethered indirect transrepression activity and antiinflammatory properties in vivo (Figs. 4 D and E and 5B).…”

“…Interestingly, potent antiinflammatory nonsteroidal compounds (NSCs) that may exhibit reduced side effects have been more recently identified (18,19). We therefore investigated whether a related NSC GR ligand (designated hereafter as CpdX) that efficiently promotes GR nuclear translocation (Fig.…”

Вивчення Протизапальної Активності Опрацьованого Крему Бетакарбокломет

“…; пригнічувати вивіль-нення еозинофілами медіаторів запалення; скорочу-вати викид вільного гістаміну; знижувати проникність мембран; індукувати утворення ліпокортинів, що мають протинабрякову активність [18]. Таким чином, проведене вивчення впливу розробленого крему Бе-такарбокломет на процеси запалення дозволяють вважати, що МЛЗ має виражену протизапальну дію (гальмує розвиток серотонінового набряку).…”