TY - JOUR T1 - In vivo Pharmacological Characterization of TD-4208, a Novel Lung Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.113.203554 SP - jpet.113.203554 AU - M. Teresa R Pulido-Rios AU - Alexander McNamara AU - Glenmar P. Obedencio AU - Yuhua Ji AU - Sarah Jaw-Tsai AU - William J Martin AU - Sharath Hegde Y1 - 2013/01/01 UR - http://jpet.aspetjournals.org/content/early/2013/05/17/jpet.113.203554.abstract N2 - Tiotropium is currently the only once-daily, long-acting muscarinic antagonist (LAMA) approved in the US and other countries for the treatment of COPD. Glycopyrronium has shown promise as a LAMA and was recently approved for once-daily maintenance treatment for 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 (ACh)-induced bronchoconstriction for up to 24 hr. In anesthetized rats, inhaled TD-4208 exhibited dose-dependent 24 hr bronchoprotection against methacholine (MCh)-induced bronchoconstriction. The estimated 24 hr potency (expressed as concentration of dosing solution) was 45.0 μg/ml. The bronchoprotective potencies of TD-4208 and tiotropium were maintained after seven 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 to marketed muscarinic receptor antagonists. ER -