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Patients with AD also suffer from behavioral and psychological symptoms of dementia that deteriorate their quality of life and lead to premature death. Currently available drugs provide modest symptomatic relief but do not reduce pathological hallmarks (senile plaques and neurofibrillary tangles) and neuroinflammation, both of which are integral parts of dementia. A large body of evidence indicates that impaired signaling pathways of cyclic-3\u2032,5\u2032- Adenosine Monophosphate (cAMP) and cyclic-3\u2032,5\u2032-guanosine Monophosphate (cGMP) may contribute to the development and progression of AD. In addition, Phosphodiesterase (PDE) inhibitors, commonly known as cAMP and\/or cGMP modulators, were found to be involved in the phosphorylation of tau; aggregation of amyloid beta; neuroinflammation; and regulation of cognition, mood, and emotion processing. The purpose of this review was to update the most recent reports on the development of novel multifunctional ligands targeting PDE as potential drugs for both symptomatic and disease-modifying therapy of AD. This review collected the chemical structures of representative multifunctional ligands, results of experimental in vitro and in vivo pharmacological studies, and current opinions regarding the potential utility of these compounds for the comprehensive therapy of AD. Finally, the multiparameter predictions of drugability of the representative compounds were calculated and discussed.<\/jats:p><\/jats:sec>","DOI":"10.2174\/0929867326666190620095623","type":"journal-article","created":{"date-parts":[[2019,7,1]],"date-time":"2019-07-01T06:52:36Z","timestamp":1561963956000},"page":"5351-5373","update-policy":"https:\/\/doi.org\/10.2174\/bsp_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer\u2019s Disease"],"prefix":"10.2174","volume":"27","author":[{"given":"Agnieszka","family":"Jankowska","sequence":"first","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Weso\u0142owska","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Paw\u0142owski","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gra\u017cyna","family":"Ch\u0142o\u0144-Rzepa","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"965","reference":[{"key":"ref=1","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.2147\/CIA.S39959","volume":"8","author":"Ferris S.H.","year":"2013","unstructured":"Ferris S.H.; Farlow M.; Language impairment in Alzheimer\u2019s disease and benefits of acetylcholinesterase inhibitors. 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