{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:06:31Z","timestamp":1792796791733,"version":"4.5.0"},"reference-count":184,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T00:00:00Z","timestamp":1721779200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Phosphodiesterase 4 (PDE4) enzymes catalyze cyclic adenosine monophosphate (cAMP) hydrolysis and are involved in a variety of physiological processes, including brain function, monocyte and macrophage activation, and neutrophil infiltration. Among different PDE4 isoforms, Phosphodiesterases 4D (PDE4Ds) play a fundamental role in cognitive, learning and memory consolidation processes and cancer development. Selective PDE4D inhibitors (PDE4Dis) could represent an innovative and valid therapeutic strategy for the treatment of various neurodegenerative diseases, such as Alzheimer\u2019s, Parkinson\u2019s, Huntington\u2019s, and Lou Gehrig\u2019s diseases, but also for stroke, traumatic brain and spinal cord injury, mild cognitive impairment, and all demyelinating diseases such as multiple sclerosis. In addition, small molecules able to block PDE4D isoforms have been recently studied for the treatment of specific cancer types, particularly hepatocellular carcinoma and breast cancer. This review overviews the PDE4DIsso far identified and provides useful information, from a medicinal chemistry point of view, for the development of a novel series of compounds with improved pharmacological properties.<\/jats:p>","DOI":"10.3390\/ijms25158052","type":"journal-article","created":{"date-parts":[[2024,7,24]],"date-time":"2024-07-24T15:47:32Z","timestamp":1721836052000},"page":"8052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["PDE4D: A Multipurpose Pharmacological Target"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7003-7891","authenticated-orcid":false,"given":"Matteo","family":"Lusardi","sequence":"first","affiliation":[{"name":"Department of Pharmacy (DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4032-323X","authenticated-orcid":false,"given":"Federica","family":"Rapetti","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3360-7146","authenticated-orcid":false,"given":"Andrea","family":"Spallarossa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-7726","authenticated-orcid":false,"given":"Chiara","family":"Brullo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy (DIFAR), University of Genoa, Viale Benedetto XV 3, 16132 Genova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1111\/j.1476-5381.2011.01729.x","article-title":"Cyclic Nucleotide Phosphodiesterase (PDE) Isozymes as Targets of the Intracellular Signalling Network: Benefits of PDE Inhibitors in Various Diseases and Perspectives for Future Therapeutic Developments","volume":"165","author":"Keravis","year":"2012","journal-title":"Br. 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