Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure–Activity Relationships

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• 作者：Jordi Gràcia ; Maria Antonia Buil ; Jordi Castro ; Peter Eichhorn ; Manel Ferrer ; Amadeu Gavaldà ; Begoña Hernández ; Victor Segarra ; Martin D. Lehner ; Imma Moreno ; Lluís Pagès ; Richard S. Roberts ; Jordi Serrat ; Sara Sevilla ; Joan Taltavull ; Miriam Andrés ; Judit Cabedo ; Dolors Vilella ; Elena Calama ; Carla Carcasona ; Montserrat Miralpeix
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 8, 2016
• 年：2016
• 卷：59
• 期：23
• 页码：10479-10497
• 全文大小：659K
• ISSN：1520-4804

文摘

Cyclic nucleotide cAMP is a ubiquitous secondary messenger involved in a plethora of cellular responses to biological agents involving activation of adenylyl cyclase. Its intracellular levels are tightly controlled by a family of cyclic nucleotide degrading enzymes, the PDEs. In recent years, cyclic nucleotide phosphodiesterase type 4 (PDE4) has aroused scientific attention as a suitable target for anti-inflammatory therapy in respiratory diseases, particularly in the management of asthma and COPD. Here we describe our efforts to discover novel, highly potent inhaled inhibitors of PDE4. Through structure based design, with the inclusion of a variety of functional groups and physicochemical profiles in order to occupy the solvent-filled pocket of the PDE4 enzyme, we modified the structure of our oral PDE4 inhibitors to reach compounds down to picomolar enzymatic potencies while at the same time tackling successfully an uncovered selectivity issue with the adenosine receptors. In vitro potencies were demonstrated in a rat lung neutrophilia model by administration of a suspension with a Penn-Century MicroSprayer Aerosolizer.