The pre-clinical pharmacology of the inhaled muscarinic antagonist GSK573719 predicts once-daily clinical dosing

Introduction: GSK573719 is a new, long-acting muscarinic antagonist offering sustained 24-h bronchodilation currently in phase III clinical trials for COPD. Objectives: To assess the pharmacology of GSK573719 in pre-clinical studies. Methods/Results: In CHO cells transfected with recombinant human M 3 receptors, GSK573719 demonstrated pM potency (–log pA 2 =23.9pM) in an acetylcholine (ACh)-mediated Ca 2+ mobilisation assay. Concentration-response curves indicated competitive antagonism with partial reversibility after drug wash out. Using isolated human bronchial strips in static tissue baths, GSK573719 was a potent, competitive antagonist (–log pA 2 =316pM) vs carbachol. Superfusion of bronchial strips with carbachol containing buffer showed that GSK573719 was slowly reversible in a concentration-dependent manner (1–100nM). Time to 50% restoration of contraction at 10nM was >600 min (vs 413 min with tiotropium bromide, 10nM). In conscious guinea pigs, GSK573719 dose-dependently blocked ACh-induced bronchoconstriction with long duration of action; a 2.5μg intratracheal dose elicited >50% bronchoprotection for >24h. Conclusions: GSK573719 is a potent muscarinic antagonist that demonstrates slow functional reversibility at cloned human M 3 receptors and at endogenous mAChR in isolated human bronchus. This profile translates into 24h duration of bronchodilation in the clinic, suitable as a once-daily treatment for COPD. Funded by GSK. *Formerly at GSK.