Discovery of M3Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease

In this paper, we report the discovery of dual M3antagonist-PDE4 inhibitor (MAPI) compounds for the inhaled treatment of pulmonary diseases. The identification of dual compounds was enabled by the intuition that the fusion of a PDE4 scaffold derived from our CHF-6001series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M3receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy ex vivo(inhibition of rat trachea contraction) and into anti-inflammatory efficacy in vitro(inhibition of TNFα release). Among the best compounds, compound 92aachieved the goal of demonstrating in vivoefficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.