In vitro pharmacological characterization of two novel dual-acting MABA compounds (LAS190792 and LAS191351)

Background This study assessed the in vitro pharmacological profile of two novel bifunctional M 3 -antagonist/β 2 -agonist (MABA) compounds in development for chronic respiratory diseases with airflow limitation. Methods Receptor binding and ß-adrenergic activity was assessed using CHO cell membranes expressing human M 1 , M 2 and M 3 , and β 1 and β 2 receptors. Electrical-field stimulated (EFS) guinea pig tracheal preparations were used to assess global functional MABA potency, onset and duration of action (DoA); functional M 3 potency (in the presence of propranolol) and β 2 potency (in resting tone [RT] preparations) were tested. β 1 activity was assessed by change in force of contraction in guinea pig left atria. Comparators were tiotropium and indacaterol. Results LAS191351 had human M 3 -receptor affinity similar to tiotropium; LAS190792 was 5-fold lower. LAS190792 was the most potent β 2 -agonist in inducing cAMP production and trachea relaxation (RT, IC 50 : 0.23 nM). Both compounds had similar or higher ß 1 /ß 2 selectivity vs indacaterol. Global potency (IC 50 : LAS190792, 1.3 nM; LAS191351, 2.6 nM) was similar to tiotropium (1.2 nM) and indacaterol (0.8 nM). Functional M 3 potency was greater for LAS191351 than LAS190792 (IC 50 : 2.8 vs 4.3 nM, respectively). Both MABAs had an onset of action faster than tiotropium; DoAs were LAS190792 206 min, LAS191351 >480 min, indacaterol 200 min and tiotropium >480 min. Conclusion LAS190792 and LAS191351 are potent and selective MABAs with different M 3 /β 2 activity in vitro . Further studies are needed to determine duration and bronchodilator efficacy of these MABAs in humans with the aim of developing a long-acting triple therapy for asthma and COPD.