by Marie-José C. van Lierop, Wynand Alkema, Anke J. Laskewitz, Rein Dijkema, Hans M. van der Maaden, Martin J. Smit, Ralf Plate, Paolo G. M. Conti, Christan G. J. M. Jans, C. Marco Timmers, Constant A. A. van Boeckel, Scott J. Lusher, Ross McGuire, Rene C. van Schaik, Jacob de Vlieg, Ruben L. Smeets, Claudia L. Hofstra, Annemieke M. H. Boots, Marcel van Duin, Benno A. Ingelse, Willem G. E. J. Schoonen, Aldo Grefhorst, Theo H. van Dijk, Folkert Kuipers, Wim H. A. Dokter
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.