{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:34:14Z","timestamp":1790393654315,"version":"4.1.0"},"reference-count":98,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T00:00:00Z","timestamp":1689379200000},"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>Cyclic nucleotide phosphodiesterases 4 (PDE4) are a family of enzymes which specifically promote the hydrolysis and degradation of cAMP. The inhibition of PDE4 enzymes has been widely investigated as a possible alternative strategy for the treatment of a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma, as well as psoriasis and other autoimmune disorders. In this context, the identification of new molecules as PDE4 inhibitors continues to be an active field of investigation within drug discovery. This review summarizes the medicinal chemistry journey in the design and development of effective PDE4 inhibitors, analyzed through chemical classes and taking into consideration structural aspects and binding properties, as well as inhibitory efficacy, PDE4 selectivity and the potential as therapeutic agents.<\/jats:p>","DOI":"10.3390\/ijms241411518","type":"journal-article","created":{"date-parts":[[2023,7,17]],"date-time":"2023-07-17T00:35:04Z","timestamp":1689554104000},"page":"11518","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["PDE4 Inhibitors: Profiling Hits through the Multitude of Structural Classes"],"prefix":"10.3390","volume":"24","author":[{"given":"Jian","family":"Jin","sequence":"first","affiliation":[{"name":"Institute of Pharmaceutical Science, King\u2019s College London, Stamford Street, London SE1 9NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mazzacuva","sequence":"additional","affiliation":[{"name":"School of Health, Sport and Bioscience, University of East London, London E15 4LZ, UK"}],"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 Department, Pharmaceutical and Nutraceutical Section, Via Ugo Schiff 6, Sesto Fiorentino, University of Florence, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paola","family":"Giovannoni","sequence":"additional","affiliation":[{"name":"Neurofarba Department, Pharmaceutical and Nutraceutical Section, Via Ugo Schiff 6, Sesto Fiorentino, University of Florence, 50019 Florence, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9711-5183","authenticated-orcid":false,"given":"Agostino","family":"Cilibrizzi","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, King\u2019s College London, Stamford Street, London SE1 9NH, UK"},{"name":"Centre for Therapeutic Innovation, University of Bath, Bath BA2 7AY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/s41573-019-0033-4","article-title":"Therapeutic targeting of 3\u2032,5\u2032-cyclic nucleotide phosphodiesterases: Inhibition and beyond","volume":"18","author":"Baillie","year":"2019","journal-title":"Nat. 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