title: Preclinical efficacy of THRX-200495, a dual pharmacology muscarinic receptor antagonist and β(2)-adrenoceptor agonist (MABA).
abstract: Combinations of a muscarinic receptor antagonist (MA) and a β(2)-adrenoceptor agonist (BA) improve bronchodilation in COPD patients to a greater extent than drugs with either mechanism alone. Here, using an in vivo model of bronchoprotection in guinea pigs, we characterize a single agent with dual-acting MA and BA activity, THRX-200495 (MABA). THRX-200495 was compared to a fixed-dose combination of a short-acting muscarinic receptor antagonist (SAMA) and a β(2)-adrenoceptor agonist (SABA). The SAMA/SABA combination consisted of a 1:5.7 ratio of ipratropium and albuterol (the components of Combivent®). Conscious guinea pigs received aqueous nebulized solutions of vehicle or test compound by aerosol exposure. Bronchoprotective potency was estimated in anesthetized, tracheotomized and ventilated guinea pigs at predetermined time points after aerosol exposure by measuring changes in ventilation pressure. The individual (MA, BA) and composite (MABA) pharmacologies were assessed by determining protection against bronchoconstrictor responses induced by methacholine in the presence of propranolol (for MA activity), histamine (for BA activity) or methacholine (MABA activity). Bronchoprotection was calculated as percent inhibition of methacholine or histamine response relative to the vehicle group. THRX-200495 exhibited matched MA (ID(50) = 11.4 μg/mL) and BA (ID(50) = 11.2 μg/mL) potency and potent dual pharmacology (MABA ID(50) = 3.5 μg/mL) that persisted for over 24 h. The combination of ipratropium/albuterol exhibited bronchoprotective activity that was 2.6-fold more potent as a BA (ID(50) = 5.7 μg/mL) than as an MA (ID(50) = 14.6 μg/mL) at 0.5 h post-dose and 37-fold more potent as an MA (ID(50) = 4.3 μg/mL) than a BA (ID(50) = 159 μg/mL) at 1.5 h post aerosol exposure. Under MABA pharmacological conditions, ipratropium/albuterol produced potent bronchoprotective activity (ID(50) = 2.0/11.4 μg/mL) and an apparent additive effect of the two pharmacologies. In conclusion, a dual-acting prototypical MABA, THRX-200495, demonstrated potent, balanced and long-lasting bronchodilation in a guinea pig model of bronchoprotection that was greater than either the MA or BA mechanisms alone.
authors: Department of Pharmacology, Theravance Inc., 901 Gateway Blvd, South San Francisco, CA 94080, USA. amcnamara@theravance.com
authors: Alexander
authors: A
authors: McNamara
authors: Tod
authors: T
authors: Steinfeld
authors: Maria Teresa
authors: MT
authors: Pulido-Rios
authors: Eric
authors: E
authors: Stangeland
authors: Sharath S
authors: SS
authors: Hegde
authors: Mathai
authors: M
authors: Mammen
authors: William J
authors: WJ
authors: Martin
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001980:Bronchi / Q000187:drug effects; D002219:Carbamates / Q000494:pharmacology*; D006168:Guinea Pigs; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D016210:Methacholine Chloride / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D002219:Carbamates; D018727:Muscarinic Antagonists; D015363:Quinolones; C580619:biphenyl-2-ylcarbamic acid 1-(3-(4-(4-(2-(2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)ethyl)phenoxy)phenyl)propyl)piperidin-4-yl ester; D016210:Methacholine Chloride