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

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.

SUBMITTER: van Lierop MJ

PROVIDER: S-EPMC3495945 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

van Lierop Marie-José C MJ Alkema Wynand W Laskewitz Anke J AJ Dijkema Rein R van der Maaden Hans M HM Smit Martin J MJ Plate Ralf R Conti Paolo G M PG Jans Christan G J M CG Timmers C Marco CM van Boeckel Constant A A CA Lusher Scott J SJ McGuire Ross R van Schaik Rene C RC de Vlieg Jacob J Smeets Ruben L RL Hofstra Claudia L CL Boots Annemieke M H AM van Duin Marcel M Ingelse Benno A BA Schoonen Willem G E J WG Grefhorst Aldo A van Dijk Theo H TH Kuipers Folkert F Dokter Wim H A WH

PloS one 20121112 11

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 dist ...[more]

PMID: 23152771

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Project description:BackgroundInhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma.MethodsThis phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 μg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 μg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control.ResultsFifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 μg, 34 received AZD7594 250 μg, and 34 received AZD7594 800 μg. AZD7594 800 μg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 μg (0.076 L -0·036-0·188, p = 0.183) and 58 μg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 μg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated.ConclusionsTwo-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594.Trial registrationClinicalTrials.gov number NCT02479412 .

Dataset Information

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

Publications

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

Similar Datasets

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