Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases

J Pharmacol Exp Ther. 2013 May;345(2):260-70. doi: 10.1124/jpet.112.202051. Epub 2013 Feb 22.

Abstract

Activation of muscarinic subtype 3 (M3) muscarinic cholinergic receptors (mAChRs) increases airway tone, whereas its blockade improves lung function and quality of life in patients with pulmonary diseases. The present study evaluated the pharmacological properties of a novel mAChR antagonist, GSK573719 (4-[hydroxy(diphenyl)methyl]-1-{2-[(phenylmethyl)oxy]ethyl}-1-azoniabicyclo[2.2.2]octane; umeclidinium). The affinity (Ki) of GSK573719 for the cloned human M1-M5 mAChRs ranged from 0.05 to 0.16 nM. Dissociation of [(3)H]GSK573719 from the M3 mAChR was slower than that for the M2 mAChR [half-life (t1/2) values: 82 and 9 minutes, respectively]. In Chinese hamster ovary cells transfected with recombinant human M3 mAChRs, GSK573719 demonstrated picomolar potency (-log pA2 = 23.9 pM) in an acetylcholine (Ach)-mediated Ca(2+) mobilization assay. Concentration-response curves indicate competitive antagonism with partial reversibility after drug washout. Using isolated human bronchial strips, GSK573719 was also potent and showed competitive antagonism (-log pA2 = 316 pM) versus carbachol, and was slowly reversible in a concentration-dependent manner (1-100 nM). The time to 50% restoration of contraction at 10 nM was about 381 minutes (versus 413 minutes for tiotropium bromide). In mice, the ED50 value was 0.02 μg/mouse intranasally. In conscious guinea pigs, intratracheal administration of GSK573719 dose dependently blocked Ach-induced bronchoconstriction with long duration of action, and was comparable to tiotropium; 2.5 μg elicited 50% bronchoprotection for >24 hours. Thus, GSK573719 is a potent anticholinergic agent that demonstrates slow functional reversibility at the human M3 mAChR and long duration of action in animal models. This pharmacological profile translated into a 24-hour duration of bronchodilation in vivo, which suggested umeclidinium will be a once-daily inhaled treatment of pulmonary diseases.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Inhalation
  • Animals
  • CHO Cells
  • Calcium / metabolism
  • Carbachol / pharmacology
  • Cholinergic Antagonists / pharmacology
  • Cricetinae
  • Cricetulus
  • Guinea Pigs
  • Kinetics
  • Lung / drug effects
  • Lung Diseases / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • Muscarinic Agonists / pharmacology
  • Muscarinic Antagonists / administration & dosage
  • Muscarinic Antagonists / therapeutic use*
  • Plethysmography
  • Quinuclidines / administration & dosage
  • Quinuclidines / therapeutic use*
  • Receptor, Muscarinic M3 / drug effects
  • Receptors, Muscarinic
  • Scopolamine Derivatives / pharmacology
  • Tiotropium Bromide

Substances

  • Cholinergic Antagonists
  • GSK573719
  • Muscarinic Agonists
  • Muscarinic Antagonists
  • Quinuclidines
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic
  • Scopolamine Derivatives
  • Carbachol
  • Calcium
  • Tiotropium Bromide