title: In vitro pharmacological characterization of vilanterol, a novel long-acting β2-adrenoceptor agonist with 24-hour duration of action.
abstract: Vilanterol trifenatate (vilanterol) is a novel, long-acting β(2)-adrenoceptor (β(2)-AR) agonist with 24 h activity. In this study, we describe the preclinical pharmacological profile of vilanterol using radioligand binding and cAMP studies in recombinant assays as well as human and guinea pig tissue systems to characterize β(2)-AR binding and functional properties. Vilanterol displayed a subnanomolar affinity for the β(2)-AR that was comparable with that of salmeterol but higher than olodaterol, formoterol, and indacaterol. In cAMP functional activity studies, vilanterol demonstrated similar selectivity as salmeterol for β(2)- over β(1)-AR and β(3)-AR, but a significantly improved selectivity profile than formoterol and indacaterol. Vilanterol also showed a level of intrinsic efficacy that was comparable to indacaterol but significantly greater than that of salmeterol. In cellular cAMP production and tissue-based studies measuring persistence and reassertion, vilanterol had a persistence of action comparable with indacaterol and longer than formoterol. In addition, vilanterol demonstrated reassertion activity in both cell and tissue systems that was comparable with salmeterol and indacaterol but longer than formoterol. In human airways, vilanterol was shown to have a faster onset and longer duration of action than salmeterol, exhibiting a significant level of bronchodilation 22 h after treatment. From these investigations, the data for vilanterol are consistent, showing that it is a novel, potent, and selective β(2)-AR receptor agonist with a long duration of action. This pharmacological profile combined with clinical data is consistent with once a day dosing of vilanterol in the treatment of both asthma and chronic obstructive pulmonary disease (COPD).
authors.affiliation: Respiratory TAU, GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Robert.X.Slack@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Slack
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Barrett
authors.forename: Valerie S
authors.initials: VS
authors.lastname: Morrison
authors.forename: Richard G
authors.initials: RG
authors.lastname: Sturton
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Emmons
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Ford
authors.forename: Richard G
authors.initials: RG
authors.lastname: Knowles
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001592:Benzyl Alcohols / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002722:Chlorobenzenes / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism; D003627:Data Interpretation, Statistical; D005454:Fluorescence Polarization; D006168:Guinea Pigs; D006801:Humans; D007700:Kinetics; D011412:Propanolamines / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D011869:Radioligand Assay; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects / Q000378:metabolism; D000068299:Salmeterol Xinafoate
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D058673:Adrenergic beta-3 Receptor Antagonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C550468:vilanterol; D000068299:Salmeterol Xinafoate; D000242:Cyclic AMP; D000420:Albuterol; C033394:CGP 12177