New Acetylcholinesterase Inhibitors for Alzheimer's Disease

Abstract

Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.

Chemical and Physical Approaches for the Treatment of Alzheimer's Disease

“…In general, AChEIs are well tolerated, but the possibility of adverse effects still exists. Different AChEIs may have different safety profiles [104]. It is believed that the benefits of the usage of AChEIs outweigh their risks and costs.…”

Translational Research in Nicotine Dependence

“…Because the actions of ACh in the synapse are terminated by degradation of the neurotransmitter by the enzyme acetylcholinesterase (AChE), an alternative approach to increase cholinergic tone in the synapse is through administration of AChE inhibitors. Inhibition of AChE is the primary mode of action of rivastigmine, donepezil, and galantamine, all of which are commonly prescribed medications for cognitive impairment and first-line medications for Alzheimer's disease (Mehta et al 2012). In nicotine-dependent animals, studies utilizing these drugs during withdrawal show that increasing endogenous ACh tone via inhibition of AChE can rescue some aspects of cognitive withdrawal deficits (Wilkinson and Gould 2011).…”

(Thiazol-2-yl)hydrazone derivatives from acetylpyridines as dual inhibitors of MAO and AChE: synthesis, biological evaluation and molecular modeling studies

“…AChE is a serine hydrolase mainly found at neuromuscular junctions and cholinergic brain synapses 21 . AD is associated with a loss of cholinergic neurons in the brain and a decreased level of AChE, thus the major therapeutic goal in the AD treatment strategies is the inhibition of brain AChE 22 . Taking into account our recent studies for the development of new MAO inhibitors in which we explained that a pyridine ring linked at N1 of the hydrazine moiety, together with the simultaneous presence of an aromatic substituent at C4 of the thiazole nucleus, could confer an inhibitory activity on hMAO enzymes 23,24 , we designed 36 (thiazol-2-yl)hydrazone derivatives of acetylpyridine regioisomers.…”