Pharmacological Profile of AZD8871 (LAS191351), a Novel Inhaled Dual M₃ Receptor Antagonist/β₂-Adrenoceptor Agonist Molecule with Long-Lasting Effects and Favorable Safety Profile

Abstract

AZD8871 is a novel muscarinic antagonist and b 2-adrenoceptor agonist in development for chronic obstructive pulmonary disease. This study describes the pharmacological profile of AZD8871 in in vitro and in vivo assays. AZD8871 is potent at the human M 3 receptor (pIC 50 in binding assays: 9.5) and shows kinetic selectivity for the M 3 (half-life: 4.97 hours) over the M 2 receptor (half-life: 0.46 hour). It is selective for the b 2-adrenoceptor over the b 1 and b 3 subtypes (3-and 6-fold, respectively) and shows dual antimuscarinic and b 2-adrenoceptor functional activity in isolated guinea pig tissue (pIC 50 in electrically stimulated trachea: 8.6; pEC 50 in spontaneous tone isolated trachea: 8.8, respectively), which are sustained over time. AZD8871 exhibits a higher muscarinic component than batefenterol in human bronchi, with a shift in potency under propranolol blockade of 2-and 6-fold, respectively, together with a persisting relaxation (5.3% recovery at 8 hours). Nebulized AZD8871 prevents acetylcholine-induced bronchoconstriction in both guinea pig and dog with minimal effects on salivation and heart rate at doses with bronchoprotective activity. Moreover, AZD8871 shows long-lasting effects in dog, with a bronchoprotective half-life longer than 24 hours. In conclusion, these studies demonstrate that AZD8871 is a dual-acting molecule with a high muscarinic component and a long residence time at the M 3 receptor; moreover, its preclinical profile in animal models suggests a once-daily dosing in humans and a favorable safety profile. Thus, AZD8871 has the potential to be a next generation of inhaled bronchodilators in respiratory diseases.

Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator

“…Navafenterol (AZD8871, formerly LAS191351) is one of the few MABAs in clinical development for the treatment of COPD. Its pharmacological profile has been extensively studied in preclinical investigations in vitro and in vivo, and these investigations have confirmed its dual action at β 2 -and muscarinic receptors [6].…”

Navafenterol (AZD8871) in healthy volunteers: safety, tolerability and pharmacokinetics of multiple ascending doses of this novel inhaled, long-acting, dual-pharmacology bronchodilator, in two phase I, randomised, single-blind, placebo-controlled studies

“…Navafenterol (AZD8871) is a novel chemical entity possessing long-acting, dual-pharmacology (muscarinic receptor antagonist and β 2− adrenoceptor agonist [MABA]) activities in a single molecule. Preclinical pharmacological characterisations of navafenterol and an earlier compound in the series, LAS190792, have been described previously [5,6]. The key structural difference between these two compounds is in the region linking the antimuscarinic and β 2 -adrenoceptor functional regions, which is an N-phenylcarbamate in navafenterol and a benzotriazole in LAS190792 [6].…”

“…Preclinical pharmacological characterisations of navafenterol and an earlier compound in the series, LAS190792, have been described previously [5,6]. The key structural difference between these two compounds is in the region linking the antimuscarinic and β 2 -adrenoceptor functional regions, which is an N-phenylcarbamate in navafenterol and a benzotriazole in LAS190792 [6]. The linker in navafenterol, in contrast to that in LAS190792, tips the balance of activities toward M 3 antagonism, resulting in a dual bronchodilator with fewer of the secondary effects associated with β-adrenoceptor agonism [6].…”

“…The key structural difference between these two compounds is in the region linking the antimuscarinic and β 2 -adrenoceptor functional regions, which is an N-phenylcarbamate in navafenterol and a benzotriazole in LAS190792 [ 6 ]. The linker in navafenterol, in contrast to that in LAS190792, tips the balance of activities toward M 3 antagonism, resulting in a dual bronchodilator with fewer of the secondary effects associated with β-adrenoceptor agonism [ 6 ]. The β 2 -adrenoceptor activity of LAS190792 is markedly higher than that of navafenterol and both compounds have low β 1 -adrenoceptor activity [ 6 ].…”

“…The linker in navafenterol, in contrast to that in LAS190792, tips the balance of activities toward M 3 antagonism, resulting in a dual bronchodilator with fewer of the secondary effects associated with β-adrenoceptor agonism [ 6 ]. The β 2 -adrenoceptor activity of LAS190792 is markedly higher than that of navafenterol and both compounds have low β 1 -adrenoceptor activity [ 6 ].…”