Novel Class of Benzoic Acid Ester Derivatives as Potent PDE4 Inhibitors for Inhaled Administration in the Treatment of Respiratory Diseases

• Published in: Journal of medicinal chemistry 2014-02, Vol.57 (3), p.793-816
• Main Authors: Armani, Elisabetta, Amari, Gabriele, Rizzi, Andrea, Fanti, Renato De, Ghidini, Eleonora, Capaldi, Carmelida, Carzaniga, Laura, Caruso, Paola, Guala, Matilde, Peretto, Ilaria, La Porta, Elena, Bolzoni, Pier T, Facchinetti, Fabrizio, Carnini, Chiara, Moretto, Nadia, Patacchini, Riccardo, Bassani, Franco, Cenacchi, Valentina, Volta, Roberta, Amadei, Francesco, Capacchi, Silvia, Delcanale, Maurizio, Puccini, Paola, Catinella, Silvia, Civelli, Maurizio, Villetti, Gino
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Asthma - drug therapy; Benzoates - chemical synthesis; Benzoates - chemistry; Benzoates - pharmacology; Cell Line; Chronic Disease; Crystallography, X-Ray; Eosinophilia - drug therapy; Eosinophilia - immunology; Eosinophilia - pathology; Esters; Guinea Pigs; Humans; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Lung - drug effects; Lung - immunology; Lung - pathology; Lung Diseases, Obstructive - drug therapy; Molecular Docking Simulation; Ovalbumin; para-Aminobenzoates - chemical synthesis; para-Aminobenzoates - chemistry; para-Aminobenzoates - pharmacology; Phosphodiesterase 4 Inhibitors - chemical synthesis; Phosphodiesterase 4 Inhibitors - chemistry; Phosphodiesterase 4 Inhibitors - pharmacology; Protein Conformation; Rats; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm401549m

The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.