Edited by Ana Martinez Gil
From the Preface
Alzheimer´s disease (AD) is the most prevalent type of neurodegenerative disorder in the elderly. Pathological hallmarks of this progressive dementia include extra cellular plaques of b-amyloid, intracellular neurofibrillary tangles of hyperphosphorylated tau protein and loss of cholinergic neurons in the basal forebrain.
A recent study from Bloomberg School of Public Health has estimated that more than 26 million people worldwide were living with AD in 2006 and that the global prevalence of the disease will grow to more than 106 million by 2050. By that time, 43 per cent of those with AD will need high-level care, equivalent to that of a nursing home. However, if even modest advances in preventing AD or delaying its progression are made, it could have a huge global public health impact. According to this study, interventions that could delay the onset of AD by as little as one year would reduce prevalence of the disease by 12 million fewer cases in 2050. These data revealed the great importance and the social need of finding an effective therapeutic intervention for AD.
This book collects some of the most outstanding examples under current pharmaceutical development trying to reach the Alzheimer´s drug market in the next years with the aim of helping the scientific community in the discovery of effective therapies for this devastating disease.
Beyond the cholinergic hypothesis, that provide acetylcholinesterase inhibitors as the first palliative treatment available up to date for those patients, there are several innovative approaches for new drug discovery based in the crosstalk between the cholinergic system and others pathological pathways such as apoptosis and/or b-amyloid processing. Part A of this book contains six chapters dealing with more than cholinergic drugs. Among them, ladostigil is one of these examples. It is a multifunctional drug designed to target simultaneously acetylcholinesterase and monoamino-oxydasa-B, which is under investigations for use in treating AD, Parkinson´s disease as well as depressive illness. Currently phase II clinical trials are undergoing. Furthermore, a new line of research has emerged over the last several years focused on the design synthesis and pharmacological evaluation of dual binding site acetylcholinesterase (AChE) inhibitors that simultaneously bind to the catalytic and peripheral anionic sites (PAS) of AChE. The ability of the inhibitors to interact with the two sites on AChE should confer additional biological properties aimed at targeting several early events in the AD neurotoxic cascade such the inhibition of b-amyloid aggregation. Memoquin and NP-0361 are the most advances drug candidates in this class where phase I clinical trials have already been initiated for the later. Combination into a single molecule of fragments derived from different AChE inhibitors, leds to the so-called huprines (a structural mixture of (-)-huprine and tacrine). Hit-to-lead optimization in this novel class of AChE inhibitors has allowed the development of some huprines as multipotent compounds endowed with a set of both cholinergic and non-cholinergic pharmacological effects which made them very promising drug candidates for Alzheimer’s disease, as well as for other neurodegenerative disorders. Finally, different pharmacological receptor emerged as new disease-modifying targets for AD. This is the case for BuChE inhibitors, M1 muscarinic agonist and a7 nicotinic agonist. Several compounds belonging to these classes of pharmacological drugs are on clinical trials and the results from them are expected to validate new targets for AD.
Part B of this book is focused on two different examples of searching new drugs based on the amyloid hypothesis. The discovery, development and therapeutic effect of beta-sheet breaker molecules and anti-aggregation agents able to remove amyloid toxic elements in Alzheimer’s disease are described here in. A special mention is done to Alzhemed which completed clinical phase III in USA without outstanding results. Moreover, an extensive revision to g-secretase inhibitors is done, with emphasis in compounds currently in advanced clinical trials such as Flurizan, or recently started clinical development such as LY450139 and NGX267.
Finally, the Part C of this book is dedicated to the few therapeutic strategies based on tau pathology that have started clinical trials. Inhibitors of glycogen synthase kinase 3 (GSK-3) are here described as a promising disease modifying therapeutic strategy and the case of TDZDS and its most advanced candidate, called NP-12, is here presented as a successful example of early research.
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