TY - JOUR
T1 - Org 214007-0
T2 - A Novel Non-Steroidal Selective Glucocorticoid Receptor Modulator with Full Anti-Inflammatory Properties and Improved Therapeutic Index
AU - van Lierop, Marie José C.
AU - Alkema, Wynand
AU - Laskewitz, Anke J.
AU - Dijkema, Rein
AU - van der Maaden, Hans M.
AU - Smit, Martin J.
AU - Plate, Ralf
AU - Conti, Paolo G.M.
AU - Jans, Christan G.J.M.
AU - Timmers, C. Marco
AU - van Boeckel, Constant A.A.
AU - Lusher, Scott J.
AU - McGuire, Ross
AU - van Schaik, Rene C.
AU - de Vlieg, Jacob
AU - Smeets, Ruben L.
AU - Hofstra, Claudia L.
AU - Boots, Annemieke M.H.
AU - van Duin, Marcel
AU - Ingelse, Benno A.
AU - Schoonen, Willem G.E.J.
AU - Grefhorst, Aldo
AU - van Dijk, Theo H.
AU - Kuipers, Folkert
AU - Dokter, Wim H.A.
PY - 2012/11/12
Y1 - 2012/11/12
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84869055083
U2 - 10.1371/journal.pone.0048385
DO - 10.1371/journal.pone.0048385
M3 - Article
C2 - 23152771
SN - 1932-6203
VL - 7
JO - PLoS ONE
JF - PLoS ONE
IS - 11
M1 - e48385
ER -