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This study aims to identify and evaluate novel PDE4 inhibitors for anti-inflammatory therapy.

February 19, 2026Molecules0 citationsOpen Access

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

CVClaudia VergelliUniversity of Florence LCLetizia CrocettiUniversity of Florence GGGabriella GuerriniUniversity of Florence

Key Points

This study aims to identify and evaluate novel PDE4 inhibitors for anti-inflammatory therapy.
Synthesis of 5-acetyl-2-ethyl-6-phenyl-3(2H)-pyridazinones
Evaluation of selectivity toward PDE4A4 and PDE4D3
Assessment of TNFα production inhibition in human whole blood
In vitro metabolism testing and in vivo studies on selected compounds
Molecular docking of ligands with enzyme complexes
Identified compounds with potent PDE4B1 inhibition in the low nanomolar range
Demonstrated selectivity against PDE4A4 and PDE4D3
Two compounds (3a and 3k) showed significant potential through further testing

Abstract

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 (3a and 3k) 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.

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