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

LAS190792 is a novel muscarinic antagonist and β₂-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 M₃ receptor (pIC₅₀: 8.8 in binding assays). It is selective for the β₂-adrenoceptor over the β₁-and β₃-adrenoceptor, and shows a functional potency in a similar range to batefenterol and LABA compounds (pEC₅₀ 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 (pIC₅₀ 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 β₂-adrenoceptor agonist that has the potential to be a next generation bronchodilator with long-lasting effects and wide safety margin in humans.

Batefenterol ethane disulfonate (PubChem CID 11629376); Bronchodilator; COPD; Long-acting muscarinic antagonist; Long-acting β(2)-adrenoceptor agonist; indacaterol maleate (PubChem CID 6918554); olodaterol free base (PubChem CID 11504295); propranolol hydrochloride (PubChem CID 62882); tiotropium bromide (PubChem CID 5487426).