P11467: An Orally-Active Acetylcholinesterase Inhibitor and α2-Adrenoceptor Antagonist for Alzheimer’s Disease

1997 ◽  
pp. 251-255
Author(s):  
Hugo M. Vargas ◽  
Craig P. Smith ◽  
Mary Li ◽  
Gina M. Bores ◽  
Andrew Giovanni ◽  
...  
Author(s):  
Zeba Firdaus ◽  
Tryambak Deo Singh

: Alzheimer’s disease (AD) is an age-associated nervous system disorder and a leading cause of dementia worldwide. Clinically it is described by cognitive impairment, and pathophysiologically by deposition of amyloid plaques and neurofibrillary tangles in the brain and neurodegeneration. This article reviews the pathophysiology, course of neuronal degeneration, and the various possible hypothesis of AD progression. These hypotheses include amyloid cascade, tau hyperphosphorylation, cholinergic disruption, metal dysregulation, vascular dysfunction, oxidative stress, and neuroinflammation. There is an exponential increase in the occurrence of the AD in recent few years that indicate an urgent need to develop some effective treatment. Currently, only 2 classes of drugs are available for AD treatment namely acetylcholinesterase inhibitor and NMDA receptor antagonist. Since AD is a complex neurological disorder and these drugs use a single target approach, alternatives are needed due to limited effectiveness and unpleasant side-effects of these drugs. Currently, plants have been used for drug development research especially because of their multiple sites of action and fewer side effects. Uses of some herbs and phytoconstituents for the management of neuronal disorders like AD have been documented in this article. Phytochemical screening of these plants shows the presence of many beneficial constituents like flavonoids, triterpenes, alkaloids, sterols, polyphenols, and tannins. These compounds show a wide array of pharmacological activities such as anti-amyloidogenic, anticholinesterase, and antioxidant. This article summarizes the present understanding of AD progression and gathers biochemical evidence from various works on natural products that can be useful in the management of this disease.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tomohiro Onishi ◽  
Ryouta Maeda ◽  
Michiko Terada ◽  
Sho Sato ◽  
Takahiro Fujii ◽  
...  

AbstractAccumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize N-[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.


2019 ◽  
Vol 21 (25) ◽  
pp. 13578-13589 ◽  
Author(s):  
Shibaji Ghosh ◽  
Kalyanashis Jana ◽  
Bishwajit Ganguly

Donepezil, an acetylcholinesterase inhibitor, is an approved drug for the symptomatic treatment of Alzheimer's disease (AD).


2016 ◽  
Vol 249 ◽  
pp. 1-9 ◽  
Author(s):  
Mullah Muhaiminul Islam ◽  
Arun Bahadur Gurung ◽  
Atanu Bhattacharjee ◽  
Kripamoy Aguan ◽  
Sivaprasad Mitra

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