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Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases

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journal contribution
posted on 04.12.2017, 00:00 by Laura Carzaniga, Gabriele Amari, Andrea Rizzi, Carmelida Capaldi, Renato De Fanti, Eleonora Ghidini, Gino Villetti, Chiara Carnini, Nadia Moretto, Fabrizio Facchinetti, Paola Caruso, Gessica Marchini, Loredana Battipaglia, Riccardo Patacchini, Valentina Cenacchi, Roberta Volta, Francesco Amadei, Alice Pappani, Silvia Capacchi, Valentina Bagnacani, Maurizio Delcanale, Paola Puccini, Silvia Catinella, Maurizio Civelli, Elisabetta Armani
Phosphodiesterase 4 (PDE4) is a key cAMP-metabolizing enzyme involved in the pathogenesis of inflammatory disease, and its pharmacological inhibition has been shown to exert therapeutic efficacy in chronic obstructive pulmonary disease (COPD). Herein, we describe a drug discovery program aiming at the identification of novel classes of potent PDE4 inhibitors suitable for pulmonary administration. Starting from a previous series of benzoic acid esters, we explored the chemical space in the solvent-exposed region of the enzyme catalytic binding pocket. Extensive structural modifications led to the discovery of a number of heterocycloalkyl esters as potent in vitro PDE4 inhibitors. (S*,S**)-18e and (S*,S**)-22e, in particular, exhibited optimal in vitro ADME and pharmacokinetics properties and dose-dependently counteracted acute lung eosinophilia in an experimental animal model. The optimal biological profile as well as the excellent solid-state properties suggest that both compounds have the potential to be effective topical agents for treating respiratory inflammatory diseases.