Uses
Batefenterol (GSK961081;TD-5959) is a novel muscarinic receptor antagonist and β2-adrenoceptor agonist; displays high affinity for hM2, hM3 muscarinic and hβ2-adrenoceptor with Ki values of 1.4, 1.3 and 3.7 nM, respectively.
in vivo
In the guinea pig bronchoprotection assay, inhaled Batefenterol produces 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 Batefenterol are evident in guinea pigs via MA, BA, and MABA mechanisms for up to 7 days after dosing[1]. In guinea pig isolated trachea expressing native muscarinic M3 and β2, batefenterol produces smooth muscle relaxation through a dual mechanism involving competitive antagonism of the M3 receptor (EC50=50 nM) and agonism of the β2 receptor (EC50=25 nM). The combined effect on both muscarinic receptors and β2 receptors is more potent than either function working alone (EC50=10 nM). Batefenterol exhibits a rapid rate of clearance and short half-life[2].
References
[1] Hegde SS, et al. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and β2-adrenoceptor agonist properties. J Pharmacol Exp Ther. 2014 Oct;351(1):190-9. DOI:
10.1124/jpet.114.216861[2] Hughes AD, et al. Discovery of (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 (TD-5959, GSK961081, batefenterol): first-in-class dual pharmacology multivalent muscarinic antagonist and β agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD). J Med Chem. 2015 Mar 26;58(6):2609-22. DOI:
10.1021/jm501915g
