CHF6366: characterisation of the bronchoprotective effect of a novel MABA compound in the experimental bronchospasm model in anaesthetised guinea pigs

The bronchoprotective effect of CHF6366, a novel dual antimuscarinic and β2 receptor-agonist (MABA) compound, was studied in a model of bronchospasm in anaesthetised guinea pigs that allows discrimination of the two pharmacological activities by using the spasmogens acetylcholine (ACh, -/+ β2 blocker for the assessment of the MABA and antimuscarinic effect, respectively) and histamine (β2 effect). Batefenterol, a reference MABA, was included in the study as a comparator. CHF6366 (0.3-1nmol/kg), administered intratracheally, exerted a dose-dependent prevention of ACh-induced bronchospasm at 1 hour post-administration with maximal efficacy at 1nmol/kg (92.9±2.9% inhibition) and good balance of the two activities (% inhibition M3: 83.9±4.5; β2: 72.7±4.4). CHF6366 peak effect was observed at 5 minutes post-dose with both activities fully effective within the first 15 minutes. Batefenterol was less potent and less balanced than CHF6366, exerting maximal inhibition at 3nmol/kg with a predominance of β2 activity. CHF6366 1nmol/kg, administered 24 hours before spasmogens, retained a robust and balanced residual activity (% inhibition MABA: 70.9±7.4; M3: 45.3±9.2; β2: 51.4±6.0). On the contrary, with batefenterol a slight overdose (10nmol/kg) was necessary to achieve an appreciable residual effect at 24 hours. Both CHF6366 and batefenterol did not induce significant lowering of blood potassium levels at bronchoprotective doses. In conclusion, CHF6366 is a new inhaled MABA compound with a favourable in vivo pharmacological profile holding promise as a new effective dual-acting bronchodilator for COPD.