Discovery and optimization of diarylsulfone-based dual M3-Antagonists and β2-Agonists (MABAs) as inhaled bronchodilators

Dual muscarinic antagonists and β₂-agonists (MABAs) represent a promising therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease (COPD). We report the discovery and optimization of MABAs by integrating a diarylsulfone scaffold with the hydroxyquinoline moiety of indacaterol 2 to achieve dual M₃ and β₂ activity. Through SAR studies to optimize the linker design and M₃-targeting features, a novel MABA series was realized with excellent affinity at M₃/β₂ receptors. Lead compounds 150 and 160 showed high-affinity and long-lived binding to M₃ (K_i: 1.95 nM and 1.75 nM, respectively, at 24 h) and subnanomolar β₂-agonist potency, along with excellent (EC₅₀ < 10 nM) smooth muscle relaxant activity in carbachol-stimulated guinea pig trachea rings. Moreover, after intratracheal administration, both compounds exhibited sustained in vivo bronchoprotection for 24 h in the modified Einthoven model of acute bronchoconstriction, with equivalent efficacy to the clinical-stage MABA batefenterol 9. Further development of these compounds is warranted as inhaled bronchodilators.