title: In vivo pharmacological characterization of TD-4208, a novel lung-selective inhaled muscarinic antagonist with sustained bronchoprotective effect in experimental animal models.
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.
authors.affiliation: Department of Pharmacology, Theravance, Inc., South San Francisco, CA 94080, USA. tpulidorios@theravance.com
authors.forename: M T
authors.initials: MT
authors.lastname: Pulido-Rios
authors.forename: A
authors.initials: A
authors.lastname: McNamara
authors.forename: G P
authors.initials: GP
authors.lastname: Obedencio
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.forename: S
authors.initials: S
authors.lastname: Jaw-Tsai
authors.forename: W J
authors.initials: WJ
authors.lastname: Martin
authors.forename: S S
authors.initials: SS
authors.lastname: Hegde
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000280:Administration, Inhalation; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D016084:Bronchoconstriction / Q000187:drug effects; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006024:Glycopyrrolate / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016210:Methacholine Chloride; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D010862:Pilocarpine; D051381:Rats; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000037:antagonists & inhibitors; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors; D012472:Salivation / Q000187:drug effects; D012602:Scopolamine Derivatives / Q000008:administration & dosage / Q000494:pharmacology; D000069447:Tiotropium Bromide
chemical_list: D001549:Benzamides; D001993:Bronchodilator Agents; D002219:Carbamates; D018727:Muscarinic Antagonists; D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D012602:Scopolamine Derivatives; D010862:Pilocarpine; D016210:Methacholine Chloride; C583570:revefenacin; D000109:Acetylcholine; D006024:Glycopyrrolate; D000069447:Tiotropium Bromide