title: Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties.
abstract: The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,1'-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki = 1.4 nM), hM3 muscarinic receptors (Ki = 1.3 nM) and hβ2-adrenoceptors (Ki = 3.7 nM). GSK-961081 behaved as a potent hβ2-adrenoceptor agonist (EC50 = 0.29 nM for stimulation of cAMP levels) with 440- and 320-fold functional selectivity over hβ1- and hβ3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smooth muscle relaxation through MA (EC50 = 50.2 nM), BA (EC50=24.6 nM), and MABA (EC50 = 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 = 33.9 µg/ml), BA (ED50 = 14.1 µg/ml), and MABA (ED50 = 6.4 µg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55- to 110-fold greater than that of tiotropium with respect to systemic antimuscarinic antisialagogue effects and was 10-fold greater than that of salmeterol with respect to systemic β2-adrenoceptor hypotensive effects. These preclinical findings studies suggest that GSK-961081 has the potential to be a promising next-generation inhaled lung-selective bronchodilator for the treatment of airway diseases, including chronic obstructive pulmonary disease.
authors.affiliation: Theravance, Inc., South San Francisco, California shegde@theravance.com.
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Hughes
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Tod
authors.initials: T
authors.lastname: Steinfeld
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jasper
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Tae-Weon
authors.initials: TW
authors.lastname: Lee
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: McNamara
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Martin
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: M Teresa
authors.initials: MT
authors.lastname: Pulido-Rios
authors.affiliation: Theravance, Inc., South San Francisco, California.
authors.forename: Mathai
authors.initials: M
authors.lastname: Mammen
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000420:Albuterol / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001993:Bronchodilator Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D016466:CHO Cells; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D009126:Muscle Relaxation; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding; D015363:Quinolones / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D000068299:Salmeterol Xinafoate; D012602:Scopolamine Derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000069447:Tiotropium Bromide; D014018:Tissue Distribution; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D001993:Bronchodilator Agents; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; D011943:Receptors, Adrenergic, beta; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C588122:batefenterol; D000068299:Salmeterol Xinafoate; D000242:Cyclic AMP; D000420:Albuterol; D000069447:Tiotropium Bromide