Phosphodiesterase (PDE) is a superfamily of enzymes that are responsible for the hydrolysis of two second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). PDE inhibition promotes the gene transcription by activating cAMP-response element binding protein (CREB), initiating gene transcription of brain-derived neurotrophic factor (BDNF). The procedure exerts neuroprotective profile, and motor and cognitive improving efficacy. From this point of view, PDE inhibition will provide a promising therapeutic strategy for treating neurodegenerative disorders. Herein, we summarized the PDE inhibitors that have entered the clinical trials or been discovered in recent five years. Well-designed clinical or preclinical investigations have confirmed the effectiveness of PDE inhibitors, such as decreasing Aß oligomerization and tau phosphorylation, alleviating neuro-inflammation and oxidative stress, modulating neuronal plasticity and improving long-term cognitive impairment.
Neurodegenerative Diseases , Phosphodiesterase Inhibitors , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/metabolism , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/chemistry , Phosphodiesterase Inhibitors/therapeutic use , Animals , Neuroprotective Agents/pharmacology , Neuroprotective Agents/chemistry , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Phosphoric Diester Hydrolases/metabolism , Molecular Structure
Triazole scaffolds, a series of 5-membered heterocycles, are well known for their high efficacy, low toxicity, and superior pharmacokinetics. Alzheimer's disease (AD) is the first neurodegenerative disorder with complex pathological mechanisms. Triazole, as an aromatic group with three nitrogen atoms, forms polar and non-polar interactions with diverse key residues in the receptor-ligand binding procedure, and has been widely used in the molecular design in the development of anti-AD agents. Moreover, considering the simple synthesis approaches, triazole scaffolds are commonly used to link two pharmacodynamic groups in one chemical molecule, forming multi-target directed ligands (MTDLs). Furthermore, the click reaction between azide- and cyano-modified enzyme and ligand provides feasibility for the new modulator discovery, compound tissue distribution evaluation, enzyme localization, and pharmacological mechanism study, promoting the diagnosis of AD course.
Alzheimer Disease , Humans , Alzheimer Disease/diagnosis , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Ligands , Triazoles/therapeutic use , Protein Binding , Cholinesterase Inhibitors/chemistry
