Pharmacologic Characterization of GSK-961081 (TD-5959), a First-in-Class Inhaled Bifunctional Bronchodilator Possessing Muscarinic Receptor Antagonist and b2-Adrenoceptor Agonist Properties

The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl) ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin-4-yl [1,19-biphenyl]-2-ylcarbamate], a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist (MA) and b2-adrenoceptor agonist (BA) properties (MABA). In competition radioligand binding studies at human recombinant receptors, GSK-961081 displayed high affinity for hM2 (Ki5 1.4 nM), hM3 muscarinic receptors (Ki 5 1.3 nM) and hb2-adrenoceptors (Ki5 3.7 nM). GSK-961081 behaved as a potent hb2-adrenoceptor agonist (EC505 0.29 nM for stimulation of cAMP levels) with 440and 320-fold functional selectivity over hb1and hb3-adrenoceptors, respectively. In guinea pig isolated tracheal tissues, GSK-961081 produced smoothmuscle relaxation throughMA (EC505 50.2 nM), BA (EC50524.6 nM), and MABA (EC50 5 11 nM) mechanisms. In the guinea pig bronchoprotection assay, inhaled GSK-961081 produced potent, dose-dependent inhibition of bronchoconstrictor responses via MA (ED50 5 33.9 mg/ml), BA (ED50 5 14.1 mg/ml), and MABA (ED50 5 6.4 mg/ml) mechanisms. Significant bronchoprotective effects of GSK-961081 were evident in guinea pigs via MA, BA, and MABAmechanisms for up to 7 days after dosing. The lung selectivity index of GSK-961081 in guinea pigs was 55to 110fold 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 b2-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.