Novel chelators targeting cell cycle arrest, acetylcholinesterase, and monoamine oxidase for Alzheimer's therapy.
The recent finding that acetylcholinesterase (AChE) colocalizes with β-amyloid (Aβ), promotes and accelerates Aβ aggregation has renewed an intense interest in developing new multitarget AChE inhibitors as potential disease-modifying drugs for Alzheimer's therapy. In this review, we first briefly discuss the linkage and complex interplay among the three characteristic hallmarks of Alzheimer's disease (AD): amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and cholinergic hypofunction. We then review the recent studies on the four marketed cholinesterase inhibitors in term of their multiple activities, potential disease-modifying effects, and the underlying mechanisms of these actions. We finally focus on a new emerging strategy or multitarget AChE inhibitors as effective drugs for AD therapy. We explore some examples of multitarget ChE inhibitors developed in our own and other laboratories, which were purposely designed to address multiple AD etiological targets. These new AChE inhibitors hold great promise for improving cognitive functions in AD patients, slowing down the disease progression, as well as treating behavior problems related to AD.
Department of Medicinal Chemistry, Intra-cellular Therapies Inc., New York, NY 10032, USA. hzheng@intracellulartherapies.com
Hailin
H
Zheng
Mati
M
Fridkin
Moussa B H
MB
Youdim
D000110:Acetylcholinesterase / Q000378:metabolism*; D000544:Alzheimer Disease / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D008996:Monoamine Oxidase Inhibitors; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase