In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models
| Autor: | S. Jaw-Tsai, MT Pulido-Rios, Sharath S. Hegde, William J. Martin, Yuhua Ji, Alexander McNamara, Glenmar P. Obedencio |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
medicine.drug_class Bronchoconstriction Scopolamine Derivatives Muscarinic Antagonists Pharmacology Rats Sprague-Dawley Dogs Bronchodilator Administration Inhalation medicine Animals Potency media_common.cataloged_instance Dosing Tiotropium Bromide European union Lung Methacholine Chloride media_common Receptor Muscarinic M3 COPD Dose-Response Relationship Drug business.industry Receptor Muscarinic M1 Pilocarpine Muscarinic antagonist Tiotropium bromide medicine.disease Glycopyrrolate Acetylcholine Bronchodilator Agents Rats Benzamides Molecular Medicine Carbamates medicine.symptom Salivation business medicine.drug |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 346:241-250 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.113.203554 |
| Popis: | Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the United States and other countries for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment of COPD in the European Union. Here, we describe the in vivo preclinical efficacy and lung selectivity of a novel inhaled muscarinic antagonist, TD-4208 (biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester) and compare its profile to tiotropium and glycopyrronium. In anesthetized dogs, TD-4208, along with tiotropium and glycopyrronium, produced sustained inhibition of acetylcholine-induced bronchoconstriction for up to 24 hours. In anesthetized rats, inhaled TD-4208 exhibited dose-dependent 24-hour bronchoprotection against methacholine-induced bronchoconstriction. The estimated 24-hour potency (expressed as concentration of dosing solution) was 45.0 µg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after 7 days of once-daily dosing, whereas glycopyrronium showed a 6-fold loss in potency after repeat dosing. To assess systemic functional activity using a clinically relevant readout, the antisialagogue effect of compounds was also evaluated. The calculated lung selectivity index (i.e., ratio of antisialagogue and bronchoprotective potency) of TD-4208 was superior to glycopyrronium after both single and repeat dosing regimens and was superior to tiotropium after repeat dosing. In conclusion, the in vivo preclinical profile suggests that TD-4208 has the potential to be a long-acting bronchodilator for once-daily treatment of respiratory diseases. Its greater functional selectivity for the lung in preclinical models may translate to an improved tolerability profile compared with marketed muscarinic receptor antagonists. |
| Databáze: | OpenAIRE |
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