Title:Multifunctional Ligands Targeting Phosphodiesterase as the Future Strategy for the Symptomatic and Disease-Modifying Treatment of Alzheimer’s Disease
Volume: 27
Issue: 32
Author(s): Agnieszka Jankowska, Anna Wesołowska*, Maciej Pawłowski and Grażyna Chłoń-Rzepa*
Affiliation:
- Department of Clinical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow,Poland
- Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow,Poland
Keywords:
Alzheimer's disease, behavioral and psychological symptoms of dementia, cognitive impairments, neuroinflammation,
pathological hallmarks, phosphodiesterase, PDE inhibitors, multifunctional ligands.
Abstract: Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder characterized by cognitive
impairments such as memory loss, decline in language skills, and disorientation that affects
over 46 million people worldwide. 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′,5′-
Adenosine Monophosphate (cAMP) and cyclic-3′,5′-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.
