Armani, Elisabetta; Rizzi, Andrea; Capaldi, Carmelida; De Fanti, Renato; Delcanale, Maurizio; Villetti, Gino; Marchini, Gessica; Pisano, Anna Rita; Pitozzi, Vanessa; Pittelli, Maria Gloria; Trevisani, Marcello; Salvadori, Michela; Cenacchi, Valentina; Puccini, Paola; Amadei, Francesco; Pappani, Alice; Civelli, Maurizio; Patacchini, Riccardo; Baker-Glenn, Charles A. G.; Van de Poel, Herve; Blackaby, Wesley P.; Nash, Kevin; Amari, Gabriele published the artcile< Discovery of M3 Antagonist-PDE4 Inhibitor Dual Pharmacology Molecules for the Treatment of Chronic Obstructive Pulmonary Disease>, Quality Control of 85070-57-1, the main research area is M3 antagonist PDE4 inhibitor chronic obstructive pulmonary disease.
In this paper, we report the discovery of dual M3 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 CHF-6001 series with a muscarinic scaffold through a common linking ring could generate compounds active vs. both the transmembrane M3 receptor and the intracellular PDE4 enzyme. Two chem. series characterized by two different muscarinic scaffolds were investigated. SAR optimization was aimed at obtaining M3 nanomolar 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 92a achieved the goal of demonstrating in vivo efficacy and duration of action in both the bronchoconstriction and inflammation assays in rat after intratracheal administration.
Journal of Medicinal Chemistry published new progress about Anti-inflammatory agents. 85070-57-1 belongs to class bromides-buliding-blocks, and the molecular formula is C9H8BrFO2, Quality Control of 85070-57-1.
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