Discovery of Potent PDE4 Inhibitors with 3(2H)-Pyridazinone Scaffold: Synthesis, In Silico Studies and In Vitro/Vivo Evaluation
Claudia Vergelli, Letizia Crocetti, Gabriella Guerrini, Fabrizio Melani, Jordi Gracia, Maria Antonia Buil, Yolanda Garrido, Lluis Pagès, Joan Taltavull, Amadeu Gavaldà, Elena Calama, Maria Paola Giovannoni
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.
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…
Genes, proteins, chemicals, diseases, species, mutations and cell lines named across the full text — each resolved to its canonical identifier and authoritative record.
Click any figure to enlarge with its caption.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Figure 11
Figure 12
Figure 13
Figure 14
Figure 15
Figure 16
Figure 17
Figure 18
Figure 19
Figure 20
Figure 21
Figure 22
Figure 23
Figure 24
Figure 25
Figure 26
Figure 27
Figure 28
Figure 29
Figure 30
Figure 31
Figure 32
Figure 33
Figure 34
Figure 35
Figure 36
Figure 37
Figure 38
Figure 39Peer Reviews
No public reviews on file for this paper yet. If you reviewed it on a platform where reviews are public (OpenReview, ICLR, NeurIPS, ICML), you can paste yours below so the community can read it here.
Videos
No videos yet. Explain this paper in a talk, walkthrough, or lecture? Add one.
Taxonomy
TopicsPhosphodiesterase function and regulation · Pharmaceutical Quality and Counterfeiting · Phenothiazines and Benzothiazines Synthesis and Activities