Optimization of M₃ Antagonist-PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD

Aiming at the inhaled treatment of pulmonary diseases,the optimizationprocess of the previously reported MAPI compound 92a isherein described. The project was focused on overcoming the chemicalstability issue and achieving a balanced bronchodilator/anti-inflammatoryprofile in rats in order to be confident in a clinical effect withouthaving to overdose at one of the biological targets. The chemicalstrategy was based on fine-tuning of the substitution pattern in themuscarinic and PDE4 structural portions of the dual pharmacology compounds,also making use of the analysis of a proprietary crystal structurein the PDE4 catalytic site. Compound 10f was identifiedas a chemically stable, potent, and in vivo balancedMAPI lead compound, as assessed in bronchoconstriction and inflammationassays in rats after intratracheal administration. After the in-depthinvestigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.