Discovery of Potent PDE4 Inhibitors with 3(2H)-Pyridazinone Scaffold: Synthesis, In Silico Studies and In Vitro/Vivo Evaluation

Phospodiesterase 4 (PDE4) has long been an attractive target not only for the anti-inflammatory therapy in respiratory diseases, but also for other pathologies such as psoriatic arthritis and atopic dermatitis. In this study, we report the synthesis of 5-acetyl-2-ethyl-6-phenyl-3(2H)-pyridazinones differently substituted at position 4 with a variety of aryl/alkylamines, which act as potent PDE4B1 inhibitors in the low nanomolar range. The selectivity toward PDE4A4, PDE4D3 and HARBS, as well as the ability to inhibit TNFα production in human whole blood (hWB), was also evaluated for the most potent products, resulting in a small cluster of compounds with an interesting profile and two selected products (<b>3a</b> and <b>3k</b>) have been in depth investigated with additional in vitro tests on metabolism and in vivo studies. Finally, molecular docking and minimization of the ligand-enzyme complexes were carried out.