The novel inhaled glucocorticoid receptor agonist GW870086X protects against adenosine-induced bronchoconstriction in asthma

• Published in: Journal of allergy and clinical immunology Vol. 136; no. 2; pp. 501 - 502.e6
• Main Authors: Leaker, Brian R., MD, O'Connor, Brian, MD, Singh, Dave, MD, Barnes, Peter J., FRS
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2015; Elsevier Limited
• Subjects: Adenosine Monophosphate - adverse effects; Adenosine Monophosphate - antagonists & inhibitors; Administration, Inhalation; Adolescent; Adult; Allergy and Immunology; Anti-Asthmatic Agents - therapeutic use; Asthma; Asthma - drug therapy; Asthma - genetics; Asthma - immunology; Asthma - pathology; Bronchial Provocation Tests; Bronchoconstriction - drug effects; Double-Blind Method; Gene Expression; Genes; Heart rate; Humans; Hydrocortisone - urine; Male; Middle Aged; Osteocalcin - blood; Receptors, Glucocorticoid - agonists; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - immunology; Statistical analysis; Steroids - therapeutic use; Studies
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.01.034

The novel dissociated glucocorticoid GW870086X is a glucocorticoid receptor agonist with potency similar to that of fluticasone propionate in various human gene transrepression assays, which reflect the anti-inflammatory effects, but reduced activity in assays of gene transactivation, which is thought to mediate many of the adverse effects (AEs) of glucocorticoids.1,2 The preclinical profile of these dissociated glucocorticoids suggests that there is potential for improvement in the therapeutic index beyond that of the currently available inhaled corticosteroids.1-3 We investigated the potential anti-inflammatory activity of the novel dissociated glucocorticoid GW870086X in airway hyperresponsiveness, measured by the bronchoconstrictor response to inhaled adenosine monophosphate (AMP) in subjects with mild asthma. GW870086X belongs to a novel class of dissociated glucocorticoids with anti-inflammatory activity and a reduced potential for AEs as it enables the glucocorticoid receptor to transrepress but has less effect on transactivation.1,2 The anti-inflammatory actions of glucocorticoids are mainly mediated through gene transrepression, by inhibiting the action of proinflammatory transcription factors, such as NF-κB, through histone deacetylation, thereby switching off proinflammatory genes, which leads to a reduction in inflammatory proteins.1,2 In contrast, many of the AEs of corticosteroids occur through gene transactivation2,4,5; a dimer of acetylated glucocorticoid receptor binds to glucocorticoid response elements in the promoter region of steroid-sensitive genes to activate (or occasionally suppress) genes (such as AE genes).