Design and synthesis of 4, 5, 6, 7‐tetrahydro‐1H‐1, 2‐diazepin‐7‐one derivatives as a new series of Phosphodiesterase 4 (PDE4) inhibitors. Issue 1 (1st January 2017)

• Record Type: Journal Article
• Authors: Guariento, Sara; Karawajczyk, Anna; Bull, James A.; Marchini, Gessica; Bielska, Martyna; Iwanowa, Xenia; Bruno, Olga; Fossa, Paola; Giordanetto, Fabrizio
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 1(2017)
• Page Start: 24
• Page End: 29
• Publication Date: 2017-01-01
• Subjects: Phosphodiesterase 4 -- PDE4 inhibitors -- Diazepinone derivatives -- Compound library; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.040
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Phosphodiesterase 4 (PDE4) inhibitors have attractive therapeutic potential in respiratory, inflammatory, metabolic and CNS disorders. The present work details the design, chemical exploration and biological profile of a novel PDE4 inhibitor chemotype. A diazepinone ring was identified as an under-represented heterocyclic system fulfilling a set of PDE4 structure-based design hypotheses. Rapid exploration of the structure activity relationships for the series was enabled by robust and scalable two/three-steps parallel chemistry protocols. The resulting compounds demonstrated PDE4 inhibitory activity in cell free and cell-based assays comparable to the Zardaverine control used, suggesting potential avenues for their further development.