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

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• 作者：Sara Guariento^a ; Anna Karawajczyk^b ; James A. Bull^b ; Gessica Marchini^c ; Martyna Bielska^b ; Xenia Iwanowa^b ; Olga Bruno^a ; Paola Fossa^a ; Fabrizio Giordanetto^b ; ^{fabrizio.giordanetto@deshawresearch.com}
• 关键词：Phosphodiesterase 4 ; PDE4 inhibitors ; Diazepinone derivatives ; Compound library
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：27
• 期：1
• 页码：24-29
• 全文大小：2062 K
• 卷排序：27

文摘

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.