title: Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases.
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.
authors: GlaxoSmithKline Pharmaceuticals, King of Prussia, Pennsylvania, USA.
authors: Michael
authors: M
authors: Salmon
authors: Mark A
authors: MA
authors: Luttmann
authors: James J
authors: JJ
authors: Foley
authors: Peter T
authors: PT
authors: Buckley
authors: Dulcie B
authors: DB
authors: Schmidt
authors: Miriam
authors: M
authors: Burman
authors: Edward F
authors: EF
authors: Webb
authors: Christopher J
authors: CJ
authors: DeHaas
authors: Charles J
authors: CJ
authors: Kotzer
authors: Victoria J
authors: VJ
authors: Barrett
authors: Robert J
authors: RJ
authors: Slack
authors: Henry M
authors: HM
authors: Sarau
authors: Michael R
authors: MR
authors: Palovich
authors: Dramane I
authors: DI
authors: Lainé
authors: Douglas W P
authors: DW
authors: Hay
authors: William L
authors: WL
authors: Rumsey
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D007700:Kinetics; D008168:Lung / Q000187:drug effects; D008171:Lung Diseases / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D010991:Plethysmography; D011812:Quinuclidines / Q000008:administration & dosage / Q000627:therapeutic use*; D043587:Receptor, Muscarinic M3 / Q000187:drug effects; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives / Q000494:pharmacology; D000069447:Tiotropium Bromide
chemical_list: D018680:Cholinergic Antagonists; C573971:GSK573719; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D011812:Quinuclidines; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D002217:Carbachol; D002118:Calcium; D000069447:Tiotropium Bromide