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

PLoS One. 2012;7(11):e48385. doi: 10.1371/journal.pone.0048385. Epub 2012 Nov 12.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Anti-Inflammatory Agents, Non-Steroidal / therapeutic use
  • Arthritis, Experimental / drug therapy
  • Arthritis, Experimental / genetics
  • Blood Glucose
  • Dibenzazepines / pharmacology*
  • Dibenzazepines / therapeutic use
  • Female
  • Gene Expression Regulation / drug effects
  • Humans
  • Kinetics
  • Liver / drug effects
  • Liver / enzymology
  • Male
  • Mice
  • Molecular Docking Simulation
  • Prednisolone / pharmacology
  • Prednisolone / therapeutic use
  • Protein Binding
  • Receptors, Glucocorticoid / agonists*
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / metabolism
  • Thiadiazoles / pharmacology*
  • Thiadiazoles / therapeutic use

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Blood Glucose
  • Dibenzazepines
  • N-(8-cyano-1,2,3,4,10,14b-hexahydro-10-methyl dibenzo(c,f)pyrido(1,2-a)azepin-2-yl)-4-methyl-1,2,3-thiadiazole-5-carboxamide
  • Receptors, Glucocorticoid
  • Thiadiazoles
  • Prednisolone

Grant support

The work presented in this manuscript was financially supported by Top Institute Pharma (TIPharma), a nonprofit organization that catalyzes medicine development by founding partnerships between academia and industry, and was known under projectnumber TI-106. TIPharma had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.