Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index. Areas covered: Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile. Expert opinion: Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression 'fingerprints' produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.

Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index.

Cazzola, M., Coppola, A., Rogliani, P., Matera, M. (2015). Novel glucocorticoid receptor agonists in the treatment of asthma. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 24(11), 1473-1482 [10.1517/13543784.2015.1078310].

Novel glucocorticoid receptor agonists in the treatment of asthma

CAZZOLA, MARIO;ROGLIANI, PAOLA;
2015-08-21

Abstract

Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index.
21-ago-2015
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO
English
Con Impact Factor ISI
Inhaled corticosteroids are the only drugs that effectively suppress the airway inflammation, but they can induce considerable systemic and adverse effects when they are administered chronically at high doses. Consequently, the pharmaceutical industry is still searching for newer entities with an improved therapeutic index. Areas covered: Herein, the authors review the research in the glucocorticoid field to identify ligands of the glucocorticoid receptor (GR). These ligands preferentially induce transrepression with little or no transactivating activity, in order to have a potent anti-inflammatory action and a low side-effects profile. Expert opinion: Several agents have been synthesized, but few have been tested in experimental models of asthma. Furthermore, only three (BI-54903, GW870086X and AZD5423) have entered clinical development, although the development of at least one of them (BI-54903) was discontinued. The reason for the limited success so far obtained is that the model of transactivation versus transrepression is a too simplistic representation of GR activity. It is difficult to uncouple the therapeutic and harmful effects mediated by GR, but some useful information that might change the current perspective is appearing in the literature. The generation of gene expression 'fingerprints' produced by different GR agonists in target and off-target human tissues could be useful in identifying drug candidates with an improved therapeutic ratio.
AZD5423; GW870086X; SEGRMs; asthma; glucocorticoid receptor agonists; transactivation; transrepression
AZD5423; GW870086X; SEGRMs; asthma; glucocorticoid receptor agonists; transactivation; transrepression; Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Drug Design; Humans; Inflammation; Ligands; Receptors, Glucocorticoid
Cazzola, M., Coppola, A., Rogliani, P., Matera, M. (2015). Novel glucocorticoid receptor agonists in the treatment of asthma. EXPERT OPINION ON INVESTIGATIONAL DRUGS, 24(11), 1473-1482 [10.1517/13543784.2015.1078310].
Cazzola, M; Coppola, A; Rogliani, P; Matera, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/115479
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