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J Pharmacol Exp Ther. 2014 Oct;351(1):190-9. doi: 10.1124/jpet.114.216861. Epub 2014 Aug 6.

Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties.

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Theravance, Inc., South San Francisco, California
Theravance, Inc., South San Francisco, California.


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.

[Indexed for MEDLINE]

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