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

## TL;DR

This paper presents the development of new PDE4 inhibitors with a pyridazinone structure, showing strong anti-inflammatory potential in lab and animal tests.

## Contribution

The study introduces novel PDE4B1 inhibitors with a 3(2H)-pyridazinone scaffold and evaluates their selectivity and biological activity.

## Key findings

- Compounds 3a and 3k showed potent PDE4B1 inhibition in the low nanomolar range.
- Selected compounds exhibited good selectivity toward PDE4A4, PDE4D3, and HARBS.
- In vivo and in vitro tests confirmed the compounds' anti-inflammatory potential.

## 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.