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TD-4208

Cat. No. M6127
TD-4208 Structure
Synonym:

Revefenacin; GSK1160724

Size Price Availability Quantity
2mg USD 112.5  USD125 In stock
5mg USD 180  USD200 In stock
10mg USD 292.5  USD325 In stock
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Quality Control
Biological Activity

TD-4208 is a novel long-acting muscarinic antagonist currently in clinical development for the treatment of respiratory diseases, including bronchospasm due to COPD. The purpose of our studies was to characterize the in vivo bronchoprotective and antisialagogue effect of this new agent. In two preclinical species, we showed that inhaled TD-4208 produces sustained bronchoprotective activity up to 24 hours after dosing. Moreover, after 7-day repeat dosing in rats, equieffective bronchoprotective doses of TD-4208 inhibited salivation to a much lesser extent than the other two muscarinic antagonists. Thus, TD-4208 exhibits greater lung selectivity than either tiotropium or glycopyrronium.

Protocol
Cell Experiment
Cell lines CHO-K1 (Chinese hamster ovary-K1) cell lines
Preparation method CHO-K1 (Chinese hamster ovary-K1) cell lines stably expressing hM1, hM3, M4-G16α and cM5 mAChR subtypes, respectively, were grown to near confluency in medium consisting of HAM's F-12 supplemented with 10% FBS and 250 μg mL-1 Geneticin. The chimpanzee M5 receptor was utilized as a surrogate of the human M5 due to intellectual property restrictions surrounding use of the latter in cell-based studies. Cells were gently washed and treated for 40 minutes at 37°C with the membrane permeable, calcium sensitive dye, FLUO-4AM and, following a wash, were then incubated with increasing concentrations of revefenacin for 20 minutes at 37°C. The cells were stimulated with oxotremorine at a concentration required to elicit 90% of the maximal response (EC90). The change in fluorescence was measured using a FLIPR®-Tetra.
Concentrations
Incubation time 20 minutes
Animal Experiment
Animal models Dogs
Formulation
Dosages 3, 10, and 30 µg/kg
Administration i.v.
Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)
Species Mouse Rat Rabbit Guinea pig Hamster Dog
Weight (kg) 0.02 0.15 1.8 0.4 0.08 10
Body Surface Area (m2) 0.007 0.025 0.15 0.05 0.02 0.5
Km factor 3 6 12 8 5 20
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Chemical Information
Molecular Weight 597.75
Formula C35H43N5O4
CAS Number 864750-70-9
Purity 99.81%
Solubility DMSO: ≥ 90 mg/mL
Storage at -20°C
References

Long acting muscarinic antagonists for the treatment of chronic obstructive pulmonary disease: a review of current and developing drugs.
Mastrodicasa MA, et al. Expert Opin Investig Drugs. 2017 Feb;26(2):161-174. PMID: 28004591.

In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models.
Pulido-Rios MT, et al. J Pharmacol Exp Ther. 2013 Aug;346(2):241-50. PMID: 23685545.

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  Catalog
Abmole Inhibitor Catalog 2017




Keywords: TD-4208, Revefenacin; GSK1160724 supplier, AChR/AChE, inhibitors

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