Discovery of M<sub>3</sub> Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease.
Armani E, Rizzi A, Capaldi C, De Fanti R, Delcanale M, Villetti G, Marchini G, Pisano AR, Pitozzi V, Pittelli MG, Trevisani M, Salvadori M, Cenacchi V, Puccini P, Amadei F, Pappani A, Civelli M, Patacchini R, Baker-Glenn CAG, Van de Poël H, Blackaby WP, Nash K, Amari G.
In this paper, we report the discovery of dual M<sub>3</sub> antagonist-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 <b>CHF-6001</b> series with a muscarinic scaffold through a common linking ring could generate compounds active versus both the transmembrane M<sub>3</sub> receptor and the intracellular PDE4 enzyme. Two chemical series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M<sub>3</sub> nanomolar affinity coupled with nanomolar PDE4 inhibition, which translated into anti-bronchospastic efficacy <i>ex vivo</i> (inhibition of rat trachea contraction) and into anti-inflammatory efficacy <i>in vitro</i> (inhibition of TNFα release). Among the best compounds, compound <b>92a</b> achieved the goal of demonstrating <i>in vivo</i> efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.