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.
Footnotes
- Received May 5, 2014.
- Accepted August 5, 2014.
Financial support for this work was provided by Theravance, Inc.
Portions of this work were previously presented as two posters at the following conference: Pulido-Rios M, McNamara A, Kwan K, Martin W, Thomas R, Mammen M, and Hegde S (2009) TD-5959: a novel bifunctional muscarinic antagonist–β2-adrenergic agonist with potent and sustained in vivo bronchodilator activity in guinea pigs. ATS 2009: American Thoracic Society International Conference; 2009 May 15–20; San Diego, CA. Vol 179, pp A6195, American Thoracic Society, New York; and Aiyar J, Steinfeld T, Pulido-Rios MT, Chin K, Lee TW, Jasper J, Thomas R, Hegde S, Mammen M (2009) In vitro characterization of TD-5959: a novel bifunctional molecule with muscarinic antagonist and β2-adrenergic agonist activity. ATS 2009: American Thoracic Society International Conference; 2009 May 15–20; San Diego, CA. Vol 179, pp A4552, American Thoracic Society, New York.
- Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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