{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:34:05Z","timestamp":1790393645375,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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 TNF\u03b1 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.<\/jats:p>","DOI":"10.3390\/molecules31040699","type":"journal-article","created":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T13:15:35Z","timestamp":1771334135000},"page":"699","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Discovery of Potent PDE4 Inhibitors with 3(2H)-Pyridazinone Scaffold: Synthesis, In Silico Studies and In Vitro\/Vivo Evaluation"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9774-8047","authenticated-orcid":false,"given":"Claudia","family":"Vergelli","sequence":"first","affiliation":[{"name":"Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3473-2683","authenticated-orcid":false,"given":"Letizia","family":"Crocetti","sequence":"additional","affiliation":[{"name":"Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6711-7965","authenticated-orcid":false,"given":"Gabriella","family":"Guerrini","sequence":"additional","affiliation":[{"name":"Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Melani","sequence":"additional","affiliation":[{"name":"Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordi","family":"Gracia","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry Department, Evotec (France) SAS, Campus Curie, 195, Route d\u2018Espagne, 31036 Toulouse CEDEX, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonia","family":"Buil","sequence":"additional","affiliation":[{"name":"New Chemical Entities Discovery & Early Development, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yolanda","family":"Garrido","sequence":"additional","affiliation":[{"name":"New Chemical Entities Discovery & Early Development, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lluis","family":"Pag\u00e8s","sequence":"additional","affiliation":[{"name":"New Chemical Entities Discovery & Early Development, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joan","family":"Taltavull","sequence":"additional","affiliation":[{"name":"New Chemical Entities Discovery & Early Development, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-0041","authenticated-orcid":false,"given":"Amadeu","family":"Gavald\u00e0","sequence":"additional","affiliation":[{"name":"Pharmacology, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Calama","sequence":"additional","affiliation":[{"name":"Pharmacology, Almirall R&D, Carrer Laure\u00e0 Mir\u00f3 408-410, 08980 Sant Feliu de Llobregat, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0310-7850","authenticated-orcid":false,"given":"Maria Paola","family":"Giovannoni","sequence":"additional","affiliation":[{"name":"Neurofarba, Pharmaceutical and Nutraceutical Section, University of Florence, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"a005926","DOI":"10.1101\/cshperspect.a005926","article-title":"Second Messangers","volume":"8","author":"Newton","year":"2016","journal-title":"Cold Spring Harb. 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