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

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.