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Research ArticleDrug Discovery and Translational Medicine

In Vivo Pharmacological Characterization of TD-4208, a Novel Lung-Selective Inhaled Muscarinic Antagonist with Sustained Bronchoprotective Effect in Experimental Animal Models

M. T. Pulido-Rios, A. McNamara, G. P. Obedencio, Y. Ji, S. Jaw-Tsai, W. J. Martin and S. S. Hegde
Journal of Pharmacology and Experimental Therapeutics August 2013, 346 (2) 241-250; DOI: https://doi.org/10.1124/jpet.113.203554
M. T. Pulido-Rios
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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A. McNamara
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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G. P. Obedencio
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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Y. Ji
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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S. Jaw-Tsai
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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W. J. Martin
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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S. S. Hegde
Departments of Pharmacology (M.T.P.-R., A.M., W.J.M., S.S.H.), Drug Metabolism and Pharmacokinetics (G.P.O., S.J.-T.), and Medicinal Chemistry (Y.J.), Theravance, Inc., South San Francisco, California
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Abstract

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.

Footnotes

    • Received January 29, 2013.
    • Accepted May 16, 2013.
  • This work was completely funded and supported by Theravance, Inc.

  • This work was previously presented in abstract form as follows: Pulido-Rios MT, McNamara A, Kwan K, Martin W, Hegde S, Ji Y, and Mammen M (2009) TD-4208: a novel, lung-selective muscarinic antagonist with sustained bronchoprotective activity in preclinical models. Am J Respir Crit Care Med 179:A4557; and Pulido-Rios MT, McNamara A, Kwan K, Zamora F, Trumbull J, Obedencio GP, Jaw-Tsai S, Hegde S, and Martin WJ (2009) Bronchoprotective and antisialagogue effects of tiotropium after single and repeat dosing in rats. Am J Respir Crit Care Med 179:A4551.

  • dx.doi.org/10.1124/jpet.113.203554.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 346 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 346, Issue 2
1 Aug 2013
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Research ArticleDrug Discovery and Translational Medicine

Pharmacology of Lung-Selective Muscarinic Antagonist TD-4208

M. T. Pulido-Rios, A. McNamara, G. P. Obedencio, Y. Ji, S. Jaw-Tsai, W. J. Martin and S. S. Hegde
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 241-250; DOI: https://doi.org/10.1124/jpet.113.203554

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Research ArticleDrug Discovery and Translational Medicine

Pharmacology of Lung-Selective Muscarinic Antagonist TD-4208

M. T. Pulido-Rios, A. McNamara, G. P. Obedencio, Y. Ji, S. Jaw-Tsai, W. J. Martin and S. S. Hegde
Journal of Pharmacology and Experimental Therapeutics August 1, 2013, 346 (2) 241-250; DOI: https://doi.org/10.1124/jpet.113.203554
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