4‑Amino-7,8-dihydro-1,6-naphthyridin-5(6H)‑ones as Inhaled Phosphodiesterase Type 4 (PDE4) Inhibitors: Structural Biology and Structure–Activity Relationships

Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2018-03, Vol.61 (6), p.2472-2489
Main Authors: Roberts, Richard S, Sevilla, Sara, Ferrer, Manel, Taltavull, Joan, Hernández, Begoña, Segarra, Victor, Gràcia, Jordi, Lehner, Martin D, Gavaldà, Amadeu, Andrés, Miriam, Cabedo, Judit, Vilella, Dolors, Eichhorn, Peter, Calama, Elena, Carcasona, Carla, Miralpeix, Montserrat
Format: Article
Language:English
Subjects:
Administration, Inhalation
Animals
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Design
Dry Powder Inhalers
Lipopolysaccharides - pharmacology
Lung - metabolism
Male
Naphthyridines - administration & dosage
Naphthyridines - chemical synthesis
Naphthyridines - pharmacology
Neutrophils - drug effects
Phosphodiesterase 4 Inhibitors - administration & dosage
Phosphodiesterase 4 Inhibitors - chemical synthesis
Phosphodiesterase 4 Inhibitors - pharmacology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Tumor Necrosis Factor-alpha - blood
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Summary:Rational design of a novel template of naphthyridinones rapidly led to PDE4 inhibitors with subnanomolar enzymatic potencies. X-ray crystallography confirmed the binding mode of this novel template. We achieved compounds with double-digit picomolar enzymatic potencies through further structure-based design by targeting both the PDE4 enzyme metal-binding pocket and occupying the solvent-filled pocket. A strategy for lung retention and long duration of action based on low aqueous solubility was followed. In vivo efficacies were measured in a rat lung neutrophilia model by suspension microspray and dry powder administration. Suspension microspray of potent compounds showed in vivo efficacy with a clear dose–response. Despite sustained lung levels, dry powder administration performed much less well and without proper dose–response, highlighting clear differences between the two formulations. This indicates a deficiency in the low aqueous solubility strategy for long duration lung efficacy.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.7b01751