Batefenterol
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MedKoo CAT#: 319652

CAS#: 743461-65-6 (free base)

Description: Batefenterol, also known as GSK961081 and TD-5959, is a Muscarinic Antagonist and β2-Agonist possessing both muscarinic antagonist (MA) and β2-adrenoceptor agonist (BA) properties (MABA). 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.


Chemical Structure

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Batefenterol
CAS# 743461-65-6 (free base)

Theoretical Analysis

MedKoo Cat#: 319652
Name: Batefenterol
CAS#: 743461-65-6 (free base)
Chemical Formula: C40H42ClN5O7
Exact Mass: 739.2773
Molecular Weight: 740.254
Elemental Analysis: C, 64.90; H, 5.72; Cl, 4.79; N, 9.46; O, 15.13

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200.0mg USD 1250.0 Same Day
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1.0g USD 3450.0 2 Weeks
2.0g USD 5450.0 2 Weeks
5.0g USD 8950.0 2 Weeks
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Related CAS #: 945905-37-3(succinate)   743461-65-6 (free base)    

Synonym: GSK961081; GSK-961081; GSK 961081; TD-5959; TD 5959; TD5959; Batefenterol

IUPAC/Chemical Name: (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

InChi Key: URWYQGVSPQJGGB-DHUJRADRSA-N

InChi Code: InChI=1S/C40H42ClN5O7/c1-52-36-22-33(31(41)21-26(36)23-42-24-35(48)29-11-13-34(47)39-30(29)12-14-37(49)45-39)43-38(50)17-20-46-18-15-27(16-19-46)53-40(51)44-32-10-6-5-9-28(32)25-7-3-2-4-8-25/h2-14,21-22,27,35,42,47-48H,15-20,23-24H2,1H3,(H,43,50)(H,44,51)(H,45,49)/t35-/m0/s1

SMILES Code: O=C(OC1CCN(CCC(NC2=CC(OC)=C(CNC[C@H](O)C3=CC=C(O)C4=C3C=CC(N4)=O)C=C2Cl)=O)CC1)NC5=CC=CC=C5C6=CC=CC=C6

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: 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 vitro activity: The objective of the present studies was to characterize the pharmacologic properties of GSK-961081 [TD-5959; (R)-1-(3-((2-chloro4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)amino)methyl)-5-methoxyphenyl)amino)-3-oxopropyl) piperidin4-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. Reference: J Pharmacol Exp Ther. 2014 Oct;351(1):190-9. https://pubmed.ncbi.nlm.nih.gov/25100753/
In vivo activity: 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 β2adrenoceptor 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. Reference: J Pharmacol Exp Ther. 2014 Oct;351(1):190-9. https://pubmed.ncbi.nlm.nih.gov/25100753/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 67.0 90.51

Preparing Stock Solutions

The following data is based on the product molecular weight 740.254 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Hegde SS, Hughes AD, Chen Y, Steinfeld T, Jasper JR, Lee TW, McNamara A, Martin WJ, Pulido-Rios MT, Mammen M. 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. Epub 2014 Aug 6. PMID: 25100753.
In vitro protocol: 1. Hegde SS, Hughes AD, Chen Y, Steinfeld T, Jasper JR, Lee TW, McNamara A, Martin WJ, Pulido-Rios MT, Mammen M. 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. Epub 2014 Aug 6. PMID: 25100753.
In vivo protocol: 1. Hegde SS, Hughes AD, Chen Y, Steinfeld T, Jasper JR, Lee TW, McNamara A, Martin WJ, Pulido-Rios MT, Mammen M. 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. Epub 2014 Aug 6. PMID: 25100753.

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1: Ambery CL, Wielders P, Ludwig-Sengpiel A, Chan R, Riley JH. Population Pharmacokinetics and Pharmacodynamics of GSK961081 (Batefenterol), a Muscarinic Antagonist and β2-Agonist, in Moderate-to-Severe COPD Patients: Substudy of a Randomized Trial. Drugs R D. 2015 Sep;15(3):281-91. doi: 10.1007/s40268-015-0104-x. PubMed PMID: 26286203; PubMed Central PMCID: PMC4561049.

2: Hughes AD, Chen Y, Hegde SS, Jasper JR, Jaw-Tsai S, Lee TW, McNamara A, Pulido-Rios MT, Steinfeld T, Mammen M. Discovery of (R)-1-(3-((2-chloro-4-(((2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)et hyl)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 β₂ 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. Epub 2015 Feb 9. PubMed PMID: 25629394.

3: Norris V, Ambery C. Use of propranolol blockade to explore the pharmacology of GSK961081, a bi-functional bronchodilator, in healthy volunteers: results from two randomized trials. Drugs R D. 2014 Dec;14(4):241-51. doi: 10.1007/s40268-014-0060-x. PubMed PMID: 25265895; PubMed Central PMCID: PMC4269816.

4: Hegde SS, Hughes AD, Chen Y, Steinfeld T, Jasper JR, Lee TW, McNamara A, Martin WJ, Pulido-Rios MT, Mammen M. 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. Epub 2014 Aug 6. PubMed PMID: 25100753.

5: Cazzola M, Lopez-Campos JL, Puente-Maestu L. The MABA approach: a new option to improve bronchodilator therapy. Eur Respir J. 2013 Oct;42(4):885-7. doi: 10.1183/09031936.00067013. PubMed PMID: 24081753.

6: Bateman ED, Kornmann O, Ambery C, Norris V. Pharmacodynamics of GSK961081, a bi-functional molecule, in patients with COPD. Pulm Pharmacol Ther. 2013 Oct;26(5):581-7. doi: 10.1016/j.pupt.2013.03.015. Epub 2013 Mar 26. PubMed PMID: 23538170.

7: Norris V, Ambery C. Bronchodilation and safety of supratherapeutic doses of salbutamol or ipratropium bromide added to single dose GSK961081 in patients with moderate to severe COPD. Pulm Pharmacol Ther. 2013 Oct;26(5):574-80. doi: 10.1016/j.pupt.2013.03.009. Epub 2013 Mar 21. PubMed PMID: 23524017.

8: Wielders PL, Ludwig-Sengpiel A, Locantore N, Baggen S, Chan R, Riley JH. A new class of bronchodilator improves lung function in COPD: a trial with GSK961081. Eur Respir J. 2013 Oct;42(4):972-81. doi: 10.1183/09031936.00165712. Epub 2013 Feb 21. PubMed PMID: 23429913; PubMed Central PMCID: PMC3787816.

9: Cazzola M, Page C, Matera MG. Long-acting muscarinic receptor antagonists for the treatment of respiratory disease. Pulm Pharmacol Ther. 2013 Jun;26(3):307-17. doi: 10.1016/j.pupt.2012.12.006. Epub 2012 Dec 27. Review. PubMed PMID: 23274274.



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