6-((3s-4s)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl)-1-(tetrahydro-2h-pyran-4-yl)-1-5-dihydro-4h-pyrazolo(3-4-d)pyrimidin-4-one and Alzheimer-Disease

Alzheimer's disease (AD), one of the greatest threats to human health, is characterized by declined cognition and changed behavior. Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that play an important role in learning and memory are hydrolyzed by phosphodiesterases (PDEs). Most PDE isoforms are highly expressed in the brain, and the inhibition of PDEs is beneficial to counteract AD. Thus, targeting PDEs represents a therapeutic potential for this disease. So far, a variety of PDE inhibitors have been discovered with significant cognitive enhancement effects in animal models and more than ten agents have entered into clinical trials. In this review, we summarize PDE mediated cyclic nucleotide signaling pathways, PDE family members involved in AD and recent advance of PDE inhibitors in preclinical and clinical studies, trying to provide an outlook of PDE inhibitors for the treatment of AD in future.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Alzheimer Disease; Animals; Cognition; Cyclic GMP; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which is characterized by the primary risk factor, age. Several attempts have been made to treat AD, while most of them end in failure. However, with the deepening study of pathogenesis of AD, the expression of HDAC6 in the hippocampus, which plays a major role of the memory formation, is becoming worth of notice. Neurofibrillary tangles (NFTs), a remarkable lesion in AD, has been characterized in association with the abnormal accumulation of hyperphosphorylated Tau, which is mainly caused by the high expression of HDAC6. On the other hand, the hypoacetylated tubulin induced by HDAC6 is also fatal for the neuronal transport, which is the key impact of the formation of axons and dendrites. Overall, the significantly increased expression of HDAC6 in brain regions is deleterious to neuron survival in AD patients. Based on the above research, the inhibition of HDAC6 seems to be a potential therapeutic method for the treatment of AD. Up to now, various types of HDAC6 inhibitors have been discovered. This review mainly analyzes the HDAC6 inhibitors reported amid 2010-2020 in terms of their structure, selectivity and pharmacological impact towards AD. And we aim at facilitating the design and development of better HDAC6 inhibitors in the future.

Topics: Acetamides; Alzheimer Disease; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Models, Molecular; Molecular Structure; Neuroprotective Agents