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J Med Chem. 2017 Dec 28;60(24):10026-10046. doi: 10.1021/acs.jmedchem.7b01044. Epub 2017 Dec 14.

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

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Chemistry Research and Drug Design, ∥Pharmacology and Toxicology, ‡Pharmacokinetics Biochemistry and Metabolism, †Analytics and Early Formulations, #Project Leader Corporate Drug Development, and ⊥Corporate Pre-Clinical R&D Director, Chiesi Farmaceutici S.p.A , Nuovo Centro Ricerche, Largo Belloli 11/a, 43122 Parma, Italy.


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.

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