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

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 IngelseWillem G E J Schoonen, Aldo Grefhorst, Theo H van Dijk, Folkert Kuipers, Wim H A Dokter

Onderzoeksoutput: ArticleAcademicpeer review

Samenvatting

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.

Originele taal-2English
TijdschriftPLOS one
Volume7
Nummer van het tijdschrift11
DOI's
StatusPublished - 12 nov 2012

Keywords

  • biochemie

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