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Purity: ≥98%
Batefenterol (formerly known as GSK961081 and TD-5959) is a novel, potent and selective muscarinic receptor antagonist and β2-adrenoceptor agonist; it displays high affinity for hM2, hM3 muscarinic and hβ2-adrenoceptor with Ki values of 1.4, 1.3 and 3.7 nM, respectively. In patients with moderate to severe chronic obstructive pulmonary disease (COPD), batefenterol produced numerically greater improvements in the primary end point of trough FEV1 compared to salmeterol after 4 weeks of dosing in a phase 2b trial. There were also statistically and clinically significant differences between placebo and batefenterol.
| Targets |
hM3 muscarinic receptor ( Ki = 1.3 nM ); hM2 muscarinic receptor ( Ki = 1.4 nM ); hβ2-adrenoceptor ( Ki = 3.7 nM )
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| ln Vitro |
Batefenterol is a new, first-of-its-kind inhaled bifunctional compound with both muscarinic antagonist (MA) and beta2-coupling absorber (BA) properties (MABA). In competitive analyte binding studies, batfenterol showed high affinity for hM2 (Ki=1.4 nM), hM3 muscarinic receptors (Ki=1.3 nM), and hβ 2-increase receptors (Ki= 3.7 nM) Batfenterol is a potent hβ2-syntropin receptor agonist (EC50=0.29 nM for stimulating cAMP levels) with 440-fold and 320-fold functional selectivity over hβ1- and hβ3- Simultaneous receptors [1].
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| ln Vivo |
In a guinea pig protection test, Batefenterol was inhaled via the MA (ED50=33.9 μg/mL), BA (ED50= 14.1 μg/mL), and MABA (ED50=6.4 μg/mL) mechanisms. After approximately up to 7 days, Batefenterol's significant fold-protective effect on guinea pigs is evident through the MA, BA and MABA mechanisms [1]. In isolated guinea pig tracheas expressing native muscarinic M3 and β2, batfenterol produced smooth muscle through a dual mechanism involving M3 absorptive local resistance to muscarinic receptors and β2 receptors. This function is more effective (EC50=10 nM). Batfenterol has a rapid clearance and a calming half-life [2].
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| Cell Assay |
For 20 minutes at 37°C, CHO-K1 cells that have been transfected with each receptor subtype and stable are exposed to escalating batefenterol concentrations. Oxotremorine, a muscarinic agonist, stimulates the cells at an EC90 concentration. A 488 nm laser light source is used to stimulate the calcium-sensitive dye, causing it to bind to calcium and fluoresce. Oxotremorine causes a Gq-mediated calcium-release event. In order to create the concentration-response curve for batefenterol, the fluorescence change is measured using the FLIPR for three minutes, and the peak height of the fluorescence is considered the maximal response[1].
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| Animal Protocol |
Guinea pigs: Dissolve batefenterol in water. We dissect and isolate the trachea of guinea pigs. Before inducing contraction, the tracheal rings are first tensioned to 1 g and given an hour to equilibrate. This allows researchers to assess relaxant effects via MA and BA mechanisms, respectively, using submaximal concentrations of histamine (HIS; 30 µM) or methylcholine (MCh; 10 µM) in the presence of propranolol (10 µM). In tissues precontracted with MCh and without propranolol, relaxation via the MABA mechanism is assessed. Batefenterol is added cumulatively in half log increments after the contractile tone reaches a plateau. Each concentration is added after a steady-state relaxation response to the preceding concentration is achieved. The concentrations range from 0.1 nM to 100 µM. Theophylline (2.2 mM) is added to the test compound after the final concentration to achieve maximum relaxation[1].
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| References |
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| Molecular Formula |
C40H42CLN5O7
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|---|---|
| Molecular Weight |
740.2438
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| Exact Mass |
739.28
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| Elemental Analysis |
C, 64.90; H, 5.72; Cl, 4.79; N, 9.46; O, 15.13
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| CAS # |
743461-65-6
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| Related CAS # |
945905-37-3(succinate); 743461-65-6
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| Appearance |
Solid powder
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| SMILES |
COC1=CC(=C(C=C1CNC[C@@H](C2=C3C=CC(=O)NC3=C(C=C2)O)O)Cl)NC(=O)CCN4CCC(CC4)OC(=O)NC5=CC=CC=C5C6=CC=CC=C6
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| InChi Key |
URWYQGVSPQJGGB-DHUJRADRSA-N
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| 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
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| Chemical Name |
[1-[3-[2-chloro-4-[[[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1H-quinolin-5-yl)ethyl]amino]methyl]-5-methoxyanilino]-3-oxopropyl]piperidin-4-yl] N-(2-phenylphenyl)carbamate
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| Synonyms |
Batefenterol; GSK 961081; GSK961081; GSK-961081; TD5959; TD-5959; TD 5959
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~135.1 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (3.38 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (3.38 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.3509 mL | 6.7546 mL | 13.5091 mL | |
| 5 mM | 0.2702 mL | 1.3509 mL | 2.7018 mL | |
| 10 mM | 0.1351 mL | 0.6755 mL | 1.3509 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00687700 | Completed | Drug: GSK961081 Drug: Propranolol |
Pulmonary Disease, Chronic Obstructive |
Theravance Biopharma | March 10, 2008 | Phase 1 |
| NCT02573870 | Completed | Drug: Placebo Drug: Albuterol |
Pulmonary Disease, Chronic Obstructive |
GlaxoSmithKline | December 1, 2015 | Phase 2 |
| NCT00478738 | Completed | Drug: GSK961081 | Pulmonary Disease, Chronic Obstructive |
GlaxoSmithKline | June 2007 | Phase 2 |
| NCT02064504 | Completed | Drug: GSK961081 Drug: Fluticasone furoate |
Pulmonary Disease, Chronic Obstructive |
GlaxoSmithKline | February 19, 2014 | Phase 1 |
| NCT00550225 | Completed | Drug: GSK961081 matching placebo Drug: GSK961081 (Zometa) |
Pulmonary Disease, Chronic Obstructive |
Theravance Biopharma | November 29, 2007 | Phase 1 |
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