Org 214007-0: a novel non-steroidal selective glucocorticoid receptor modulator with full anti-inflammatory properties and improved therapeutic index

• Published in: PloS one Vol. 7; no. 11; p. e48385
• Main Authors: van Lierop, Marie-José C, Alkema, Wynand, Laskewitz, Anke J, Dijkema, Rein, van der Maaden, Hans M, Smit, Martin J, Plate, Ralf, Conti, Paolo G M, Jans, Christan G J M, Timmers, C Marco, van Boeckel, Constant A A, Lusher, Scott J, McGuire, Ross, van Schaik, Rene C, de Vlieg, Jacob, Smeets, Ruben L, Hofstra, Claudia L, Boots, Annemieke M H, van Duin, Marcel, Ingelse, Benno A, Schoonen, Willem G E J, Grefhorst, Aldo, van Dijk, Theo H, Kuipers, Folkert, Dokter, Wim H A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 12-11-2012; Public Library of Science (PLoS)
• Subjects: Analysis; Animal models; Animals; Anti-inflammatory agents; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Arthritis; Arthritis, Experimental - drug therapy; Arthritis, Experimental - genetics; Binding sites; Biology; Blood Glucose; Cell lines; Cells (Biology); Collagen; Diabetes therapy; Dibenzazepines - pharmacology; Dibenzazepines - therapeutic use; Drugs; Effectiveness; Endocrinology; Fasting; Female; Gene expression; Gene Expression Regulation - drug effects; Gene silencing; Genes; Glucocorticoids; Glucose; Glycogen; Health aspects; Humans; Immunomodulation; Immunosuppressive agents; In vivo methods and tests; Inflammation; Informatics; Insulin; Insulin resistance; Kinetics; Ligands; Liver; Liver - drug effects; Liver - enzymology; Male; Medicine; Metabolic disorders; Mice; Modulators; Molecular Docking Simulation; Muscles; Pediatrics; Pharmaceutical sciences; Pharmacology; Phosphatase; Prednisolone; Prednisolone - pharmacology; Prednisolone - therapeutic use; Protein Binding; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - chemistry; Receptors, Glucocorticoid - metabolism; Rodents; Side effects; Steroids (Organic compounds); Thiadiazoles - pharmacology; Thiadiazoles - therapeutic use; Toxicology; Transcription factors; Womens health; Netherlands
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0048385

Glucocorticoids (GCs) such as prednisolone are potent immunosuppressive drugs but suffer from severe adverse effects, including the induction of insulin resistance. Therefore, development of so-called Selective Glucocorticoid Receptor Modulators (SGRM) is highly desirable. Here we describe a non-steroidal Glucocorticoid Receptor (GR)-selective compound (Org 214007-0) with a binding affinity to GR similar to that of prednisolone. Structural modelling of the GR-Org 214007-0 binding site shows disturbance of the loop between helix 11 and helix 12 of GR, confirmed by partial recruitment of the TIF2-3 peptide. Using various cell lines and primary human cells, we show here that Org 214007-0 acts as a partial GC agonist, since it repressed inflammatory genes and was less effective in induction of metabolic genes. More importantly, in vivo studies in mice indicated that Org 214007-0 retained full efficacy in acute inflammation models as well as in a chronic collagen-induced arthritis (CIA) model. Gene expression profiling of muscle tissue derived from arthritic mice showed a partial activity of Org 214007-0 at an equi-efficacious dosage of prednisolone, with an increased ratio in repression versus induction of genes. Finally, in mice Org 214007-0 did not induce elevated fasting glucose nor the shift in glucose/glycogen balance in the liver seen with an equi-efficacious dose of prednisolone. All together, our data demonstrate that Org 214007-0 is a novel SGRMs with an improved therapeutic index compared to prednisolone. This class of SGRMs can contribute to effective anti-inflammatory therapy with a lower risk for metabolic side effects.