Recent advances in the multitarget‐directed ligands approach for the treatment of Alzheimer's disease

Abstract

With 27 million cases worldwide documented in 2006, Alzheimer's disease (AD) constitutes an overwhelming health, social, economic, and political problem to nations. Unless a new medicine capable to delay disease progression is found, the number of cases will reach 107 million in 2050. So far, the therapeutic paradigm one‐compound‐one‐target has failed. This could be due to the multiple pathogenic mechanisms involved in AD including amyloid β (Aβ) aggregation to form plaques, τ hyperphosphorylation to disrupt microtubule to form neurofibrillary tangles, calcium imbalance, enhanced oxidative stress, impaired mitochondrial function, apoptotic neuronal death, and deterioration of synaptic transmission, particularly at cholinergic neurons. Approximately 100 compounds are presently been investigated directed to single targets, namely inhibitors of β and γ secretase, vaccines or antibodies that clear Aβ, metal chelators to inhibit Aβ aggregation, blockers of glycogen synthase kinase 3β, enhancers of mitochondrial function, antioxidants, modulators of calcium‐permeable channels such as voltage‐dependent calcium channels, N‐methyl‐D‐aspartate receptors for glutamate, or enhancers of cholinergic neurotransmission such as inhibitors of acetylcholinesterase or butyrylcholinesterase. In view of this complex pathogenic mechanisms, and the successful treatment of chronic diseases such as HIV or cancer, with multiple drugs having complementary mechanisms of action, the concern is growing that AD could better be treated with a single compound targeting two or more of the pathogenic mechanisms leading to neuronal death. This review summarizes the current therapeutic strategies based on the paradigm one‐compound‐various targets to treat AD. A treatment that delays disease onset and/or progression by 5 years could halve the number of people requiring institutionalization and/or dying from AD. © 2011 Wiley Periodicals, Inc. Med Res Rev

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…In addition to specific protein targets, developed hybrid molecules can also incorporate antioxidant or anti-amyloid fragments [18]. Several review articles describing the status and advances of this class of MTDLs have been recently published, to whom the reader is directed for a more comprehensive discussion [19][20][21][22][23][24].…”

Perspectives for treating Alzheimer's disease: a review on promising pharmacological substances

“…quinolizidine and lycopodium alkaloids such as huperzine, which promotes competitive inhibition; isoquinolines such as aporphyrin and benzylisoquinoline, which are non-competitive compounds, and galantamine and lycorine, which are competitive; and indole alkaloids, which are divided into indole alkaloids, monoterpenes and physostigmine, which are competitive, and quaternary beta-carbolines, which are non-competitive. 18,19,25 Out of all of these, we highlight huperzine as a potent, selective and reversible inhibitor of AChE. This is used in cases of myasthenia gravis, organophosphate poisoning and schizophrenia.…”

“…Furthermore, it needs to be borne in mind that statins have a risky safety profile and there may be hepatic impairment and risk of rhabdomyolysis at doses that would be effective for continuous treatment of AD. 18,20 In a meta-analysis on separately evaluated cross-sectional and longitudinal observational studies (total of 19), the crosssectional studies showed that statins had a protective effect, and it was noted that use of statins was associated with a reduced risk of developing AD and other forms of dementia. However, progress in such studies is still restricted by bias in some of them.…”

“…However, many of these drugs present concerns regarding their safety profile, given that they are responsible for causing optic neuritis. 18,25,26 Antihypertensive agents: calcium channel blockers…”

“…10,17 In fact, success in this quest has consistently required clarification of the molecular mechanisms relating to the two best pathological pathways elucidated with regard to formation of NP and NFTs in AD cases. [18][19][20][21] …”