Drug Design and Discovery in Alzheimer's Disease

Atta-ur Rahman, Muhammad Iqbal Choudhary

• Publisher: Bentham Science Publishers
• Year: 2015
• Print ISBN: 9780128039595
• eBook ISBN: 9780128039601
• Topic: Medicine
• Subtopic: Pharmaceutical, Biotechnology & Healthcare Industry

Drug Design and Discovery in Alzheimer's Disease includes expert reviews of recent developments in Alzheimer's disease (AD) and neurodegenerative disease research. Originally published by Bentham as Frontiers in Drug Design and Discovery, Volume 6and now distributed by Elsevier, this compilation of the sixteen articles, written by leading global researchers, focuses on key developments in the understanding of the disease at molecular levels, identification and validation of molecular targets, as well as innovative approaches towards drug discovery, development, and delivery. Beginning with an overview of AD pharmacotherapy and existing blockbuster drugs, the reviews cover the potential of both natural and synthetic small molecules; the role of cholinesterases in the on-set and progression of AD and their inhibition; the role of beta-site APP clearing enzyme-1 (BACE-1) in the production of ?-amyloid proteins, one of the key reasons of the progression of AD; and other targets identified for AD drug discovery. - Edited and written by leading experts in Alzheimer's disease (AD) and other neurodegenerative disease drug development - Describes existing drugs for AD and current molecular understanding of the condition - Reviews recent advances in the field, including coverage of cholinesterases, BACE-1, and other drug development targets

Chapter 1

Pharmacotherapy of Alzheimer’s Disease: Current State and Future Perspectives

Jan Korabecny^a,b; Filip Zemek^a; Ondrej Soukup^b; Katarina Spilovska^a,b; Kamil Musilek^b,c; Daniel Jun^b,d; Eugenie Nepovimova^a,b; Kamil Kuca^b,d,* ^a Department of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic
^b University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic
^c University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic
^d Centre of Advanced Studies, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic

^* Address correspondence to Kamil Kuca: Centre of Advanced Studies, Faculty of Military Health Sciences, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic; Tel: [phone]; E-mail: [email protected]

Abstract

Alzheimer’s disease (AD) is a multifactorial disorder and apparently involves several different etiopathogenetic mechanisms. Up-to-date, there are no curative treatments or effective disease modifying therapies for AD. A strategy to enhance the cholinergic transmission by using acetylcholinesterase inhibitors (AChEIs) has been proposed more than two decades ago. Food and Drug Administration (FDA) gradually marketed these AChEIs: tacrine (1993), donepezil (1997), rivastigmine (2000) and galantamine (2001); tacrine is no longer used because of its high prevalence of hepatotoxicity. In addition to the AD cholinergic hypothesis, there is great evidence that voltage-gated, uncompetitive, N-methyl-D-aspartate (NMDA) antagonist memantine with moderate affinity can protect neurons from excitotoxicity. It was approved by FDA for treatment of moderate to severe stages of AD in 2003. Beyond symptomatic approaches there are anti-amyloid, neuroprotective and neuron-restorative strategies that hold promise of redefining the course of the disease as it is known. This contribution summarizes the main symptomatic strategies available for treating AD and future perspectives of pharmacotherapy for improving the AD course.

Keywords

Acetylcholinesterase

Alzheimer’s disease

butyrylcholinesterase

donepezil

galantamine

GSK-3β

inhibitors

memantine

metal chelators

modulators of secretases

M1 agonists

rivastigmine

statins

tacrine

1 Alzheimer’s Disease - Historic Overview

In 1906, German psychiatrist Alois Alzheimer firstly diagnosed and defined clinical-pathological syndrome that was later named Alzheimer’s disease (AD). When diagnosing the disease on one of his forty years old patient, Alois Alzheimer described observed symptoms as a rare pre-senile dementia occurring before 65 years of age. Nor did he or his colleagues distinguish this new disease from well-known and described senile dementia. Nevertheless, several symptoms which had Alzheimer described are common for majority of patients with diagnosed AD e.g. progressive memory loss, impaired cognitive function, behavioral changes, disruption of the integrity of the individual, hallucinations, impaired self-control and loss to the decline of spoken and written speech [1, 2].

The invention of the electron microscope in the 20th century led to the clarification of the histological changes in the brain characteristic for the AD particularly neuritic plaques and neurofibrillary tangles [3]. The existence of the neuritic plaques has been described no sooner than in the seventies of the twentieth century. Furthermore, the adverse effect of neuritic plaques on the neurons producing and releasing acetylcholine (ACh) were also observed. Further research led to the conclusion that these adverse effects are related directly to the enzymes associated with ACh. In particular, decrease of concentration and activity of cholineacetyltransferase (ChAT, EC 2.3.1.6) concentration and acetylcholinesterase (AChE, EC 3.1.1.7) in the limbic system and cerebral cortex were associated with the loss of cholinergic neurons in subcortical areas [4]. These findings opened a novel chapter of pharmacological research in an effort to increase ACh brain levels in the synaptic gaps. First experiments concentrated on the inhibition of AChE responsible for the degradation of ACh. The research was successful and it led to the introduction of several novel compounds into clinical practice: tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®) and galantamine (Reminyl®) [5, 6].

2 Current Status and Prevalence of AD

AD is one of the most common forms of dementia. The unpredictability and yet unknown etiology makes it increasingly disturbing problem for humanity, not just in terms of health, but also in terms of social and economic parameters. Furthermore, AD is a fatal illness as every person dies after 3-10 years from being diagnosed [1, 2].

Globally, AD is the fifth cause of death among people over 65 years. Cases of death caused by AD are increasing dramatically. Between 2000 and 2008 there were 66% of deaths caused by AD alone. However, cases of death due to heart failure, strokes and prostate cancer were only 13%, 20%, 8% respectively [2, 7].

In United States of America, it is estimated that 5.4 million people have been diagnosed with AD and 200000 of them are under 65 years of age (early AD onset). The total number of patients with dementia in the world is currently estimated to be around 35.6 million people. By 2050, this number is expected to increase up to 115.4 million patients [2]. The most vulnerable population are people over 85 years of age (more than 50% of AD patients). In the European Union it is estimated that from AD suffers approximately 6 million people and this figure is likely to double by 2050 [8-11]. The main reason is principally the aging population and the absence of an effective therapy. The limited understanding of the basic AD pathophysiology was the major drawback in the research of potential therapeutics. Though the tremendous progress was made in the past 30 years in the biological, biochemical, toxicological and pharmaceutical research, the considered therapeutic procedures failed or came too late in the last stage of the disease [2].

3 Risk Factors for AD

The trigger mechanism of AD is not yet fully understood, although certain risk factors contributing to the development of AD were determined. Aging population is the most threatened by AD, while it is important to note that AD is not a normal component of the aging process. People over 65 years of age display the greatest increase in the AD incidence, however even people below 65 years of age may develop AD known as early-onset AD. [5].

An important role is played by the genetic factors and heredity. It was scientifically proven that individuals with a close relative (brother, sister, parents), who were AD diagnosed are more likely to develop AD also than patients with only distant relatives suffering from AD [12, 13].

AD is genetically linked to the presence of allele ε4 of apolipoprotein E (ApoE ε4). Allele ε4 can occur in three isoforms, ε2, ε3 and ε4 however only ε4 increases the risk of AD later in life. On the other hand the presence of ε2 allele decreases the risk of developing AD [13-16].

Other risk factors include cardiovascular disease, brain injury, trauma, depression, low education level, smoking, low concentrations of folate and vitamin B12, elevated homocysteine concentra...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Preface
• List of Contributors
• Chapter 1: Pharmacotherapy of Alzheimer’s Disease: Current State and Future Perspectives
• Chapter 2: Challenges in Designing Therapeutic Agents for Treating Alzheimer’s Disease-from Serendipity to Rationality
• Chapter 3: Enzyme Inhibitors Involved in the Treatment of Alzheimer’s Disease
• Chapter 4: Towards Small Molecules as Therapies for Alzheimer’s Disease and Other Neurodegenerative Disorders
• Chapter 5: Multifunctional Enzyme Inhibition for Neuroprotection - A Focus on MAO, NOS, and AChE Inhibitors
• Chapter 6: Specific Cholinesterase Inhibitors: A Potential Tool to Assist in Management of Alzheimer Disease
• Chapter 7: Role of Acetylcholinesterase Inhibitors and Alzheimer Disease
• Chapter 8: Research Strategies Developed for the Treatment of Alzheimer’s Disease. Reversible and Pseudo-Irreversible Inhibitors of Acetylcholinesterase: Structure-Activity Relationships and Drug Design
• Chapter 9: Modulation of BACE1 Activity as a Potential Therapeutic Strategy for Treating Alzheimer’s Disease
• Chapter 10: BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease
• Chapter 11: Combining BACE1 Inhibition with Metal Chelation as Possible Therapy for Alzheimer’s Disease
• Chapter 12: Somatostatin Receptor-4 Agonists as Candidates for Treatment of Alzheimer’s Disease
• Chapter 13: Neprilysin Inhibitors Provide Insight into its Specificity and Therapeutic Potential
• Chapter 14: Targeting the GSK3β/β-catenin Signaling to Treat Alzheimer´s Disease: Plausible or Utopic?
• Chapter 15: Targets and Small Molecules Against Tauopathies. Part 1: From Genes to Soluble, Aggregation-Prone Tau Proteins
• Chapter 16: Nanomedicine Based Drug Targeting in Alzheimer’s Disease: High Impact of Small Carter
• Index