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Discovery and Optimization of Thiazolidinyl and Pyrrolidinyl Derivatives as Inhaled PDE4 Inhibitors for Respiratory Diseases
- Source :
- Journal of Medicinal Chemistry; 20240101, Issue: Preprints
- Publication Year :
- 2024
-
Abstract
- 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 vitroPDE4 inhibitors. (S*,S**)-18eand (S*,S**)-22e, in particular, exhibited optimal in vitroADME 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.
Details
- Language :
- English
- ISSN :
- 00222623 and 15204804
- Issue :
- Preprints
- Database :
- Supplemental Index
- Journal :
- Journal of Medicinal Chemistry
- Publication Type :
- Periodical
- Accession number :
- ejs44122182
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.7b01044