Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases.
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Salmon M, Luttmann MA, Foley JJ, Buckley PT, Schmidt DB, Burman M, Webb EF, DeHaas CJ, Kotzer CJ, Barrett VJ, Slack RJ, Sarau HM, Palovich MR, Laine DI, Hay DW, Rumsey WL
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.
- PubMed ID
- 23435542 [ View in PubMed]
- 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 mug/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 mug 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Umeclidinium Muscarinic acetylcholine receptor M1 Protein Humans UnknownAntagonistDetails Umeclidinium Muscarinic acetylcholine receptor M2 Protein Humans UnknownAntagonistDetails Umeclidinium Muscarinic acetylcholine receptor M3 Protein Humans YesAntagonistDetails Umeclidinium Muscarinic acetylcholine receptor M4 Protein Humans UnknownAntagonistDetails Umeclidinium Muscarinic acetylcholine receptor M5 Protein Humans UnknownAntagonistDetails