title: Novel glucocorticoid receptor agonists in the treatment of asthma.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors: a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.|b 2 University of Rome Tor Vergata, Respiratory Pharmacology Research Unit, Department of Systems Medicine , Rome, Italy mario.cazzola@uniroma2.it.|c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy.
authors: Mario
authors: M
authors: Cazzola
authors: a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.|c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy.
authors: Angelo
authors: A
authors: Coppola
authors: a 1 University of Rome Tor Vergata, Department of Systems Medicine , Rome, Italy.|c 3 University Hospital Tor Vergata, Division of Respiratory Medicine , Rome, Italy.
authors: Paola
authors: P
authors: Rogliani
authors: d 4 Second University of Naples, Unit of Pharmacology, Department of Experimental Medicine , Naples, Italy.
authors: Maria Gabriella
authors: MG
authors: Matera
mesh_terms: D000818:Animals; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008024:Ligands; D011965:Receptors, Glucocorticoid / Q000819:agonists*
chemical_list: D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D008024:Ligands; D011965:Receptors, Glucocorticoid
keywords: AZD5423; GW870086X; SEGRMs; asthma; glucocorticoid receptor agonists; transactivation; transrepression