Batefenterol-GSK961081-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemEBatefenterolCat. No.: HY-12980CAS No.: 743461-65-6Synonyms: GSK961081; TD-5959分式: CHClNO分量: 740.24作靶點(diǎn): Adrenergic Receptor; mAChR作通路: GPCR/G Protein; Neuronal Signaling儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-2

2、0C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 100 mg/mL (135.09 mM)H2O : 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (3.38 mM); Clear solution2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oil1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 2.5 mg/mL (3.38 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Batefenterol

3、 (GSK961081;TD-5959)種新的muscarinic受體拮抗劑和2-腎上腺素受體激動(dòng)劑; 對(duì)hM2，hM3和2-腎上腺素受體有親和，Ki值分別為1.4, 1.3和3.7nM。IC50 & Target Ki: 1.4 nM (hM2), 1.3 nM (hM3), 3.7 (2) 1體外研究 Batefenterol is a novel first-in-class inhaled bifunctional compound possessing both muscarinic antagonist(MA) and 2-adrenoceptor agonist (BA) pro

4、perties (MABA). In competition radioligand binding studies athuman recombinant receptors, batefenterol displays high affinity for hM2 (Ki=1.4 nM), hM3 muscarinicreceptors (Ki=1.3 nM) and h2-adrenoceptors (Ki=3.7 nM). Batefenterol behaves as a potent h2-adrenoceptor agonist (EC50=0.29 nM for stimulat

5、ion of cAMP levels) with 440- and 320-fold functionalselectivity over h1- and h3-adrenoceptors, respectively 1.體內(nèi)研究 In the guinea pig bronchoprotection assay, inhaled Batefenterol produces potent, dose-dependent inhibitionof bronchoconstrictor responses via MA (ED50=33.9 g/mL), BA (ED50=14.1 g/mL),

6、and MABA (ED50=6.4g/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 nativemuscarinic M3 and 2, batefenterol produces smooth muscle relaxation thr

7、ough a dual mechanism involvingcompetitive antagonism of the M3 receptor (EC50=50 nM) and agonism of the 2 receptor (EC50=25 nM).The combined effect on both muscarinic receptors and 2 receptors is more potent than either functionworking alone (EC50=10 nM). Batefenterol exhibits a rapid rate of clear

8、ance and short half-life 2.PROTOCOLCell Assay 1 CHO-K1 cells stably transfected with each receptor subtype are incubated with increasing concentrations ofbatefenterol for 20 minutes at 37C. The cells are stimulated with an EC90 concentration of the muscarinicagonist oxotremorine. Oxotremorine elicit

9、s a Gq-mediated calcium-release event, which in turn caused thecalcium-sensitive dye to bind to calcium and fluoresce upon stimulation with a 488 nm laser light source. Thechange in fluorescence is measured by the FLIPR for 3 minutes, and the peak height in fluorescence is takenas the maximal respon

10、se to generate the concentration-response curve for batefenterol 1.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Guinea pigs: Batefenterol is dissolved in water. Guinea pig trachea is dissected and isolated. The trachealAdministration 1 rings a

11、re initially tensioned to 1 g and allowed to equilibrate for 1 hour before evoking contraction with asubmaximal concentration of either methylcholine (MCh; 10 M), in the presence of propranolol (10 M), orhistamine (HIS; 30 M) to assess relaxant effects via MA and BA mechanisms, respectively. Relaxat

12、ionthrough the MABA mechanism is evaluated in tissues precontracted with MCh in the absence of propranolol.After the contractile tone attained a plateau, the batefenterol (0.1 nM to 100 M) is added cumulatively in halflog increments, with each concentration being added after achieving a steady-state

13、 relaxation response to2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEthe previous concentration. After the last concentration of test compound, theophylline (2.2 mM) is added toestablish maximum relaxation 1.MCE has not independently confirmed the accuracy of these methods. They are for reference

14、 only.REFERENCES1. Hegde SS, et al. Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilatorpossessing muscarinic receptor antagonist and 2-adrenoceptor agonist properties. J Pharmacol Exp Ther. 2014 Oct;351(1):190-9.2. Hughes AD, et al. Discovery

15、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 dualpharmacology multivalent muscarinic antagonist and agonist (MABA) for the treatment of chronic obstructive pulmonary disease (COPD). J MedChem