Pharmacological preclinical characterization of LAS190792, a novel inhaled bifunctional muscarinic receptor antagonist /β2-adrenoceptor agonist (MABA) molecule

Abstract LAS190792 is a novel muscarinic antagonist and β 2 -adrenoceptor agonist in development for chronic respiratory diseases. This study investigated the pharmacological profile of LAS190792 in comparison to batefenterol, tiotropium, indacaterol and olodaterol. LAS190792 is potent at the human M 3 receptor (pIC 50 : 8.8 in binding assays). It is selective for the β 2 -adrenoceptor over the β 1 -and β 3 -adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC 50 in spontaneous tone isolated trachea: 9.6). The relaxant potency of LAS190792 in electrically stimulated tissue is similar to batefenterol, with an antimuscarinic activity in presence of propranolol slightly higher than batefenterol (pIC 50 of 8.3 versus 7.9 in human tissue). LAS190792 exhibits a sustained duration of action in isolated tissue longer than that of batefenterol. Nebulized LAS190792 inhibits acetylcholine-induced bronchoconstriction in dog with minimal cardiac effects and sustained bronchodilation (t 1/2 : 13.3 h). In conclusion, these studies suggest that LAS190792 is a dual-acting muscarinic antagonist β 2 -adrenoceptor agonist that has the potential to be a next generation bronchodilator with long-lasting effects and wide safety margin in humans.