Drug Design and Discovery in Alzheimer's Disease

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.

The process of rational drug designing together with serendipity has played an important role in the search for new drugs, for example, in neurotherapeutics the dopaminergic dysfunction of Parkinson’s disease, the dopaminergic hyperfunction of schizophrenia and the acetylcholine deficit in patients suffering from Alzheimer’s disease (AD). AD is the most common form of dementia which is a group of disorders that impairs mental functioning. The aim of this chapter is 1) to analyze some examples of discoveries in AD related disorders based on some serendipitous hypotheses and rational drug design approach such as structure based drug designing, ligand based drug designing and multi-target-directed ligand approach ii) to study the drug targets such as AChE, BACE-1, Tau protein for treating AD iii) to design second-generation agents with improved efficacy and safety iv) to illustrate the complexity of problems that have to be overcome for successful targeting and v) to study drug delivery and intercellular characterization of the blood brain barrier.

Alzheimer disease (AD), a chronic and progressive neurodegenerative disease is the leading cause of dementia among older people. Several hypotheses exist on the pathogenesis of AD. According to the cholinergic hypothesis, there is an irreversible deficiency in cholinergic functions of brain resulting in substantial reduction of the neurotransmitter, acetylcholine. In contrast, amyloid hypothesis suggests that amyloid beta (Aβ) deposits are fundamental cause of the neurodegeneration. There is also an involvement of another protein, tau protein, which twists into abnormal tangles and lead to the death of brain cells. This chapter aims to provide a comprehensive review on the various enzymes involved in the pathogenic cascade of AD and their potential inhibitors. The chapter starts with a general overview on the enzymes, outlining their morphological and functional features and how they are involved in the pathogenesis of AD. The following section addresses the enzymes inhibitors at various stages of drug development, highlighting their mechanisms of action, advantages, limitations and potential clinical applications.

Neurodegenerative diseases caused by hereditary or idiosyncratic neuronal dysfunction share some phenotypic commonalities. Intracellular aggregation of proteins, metal dyshomeostasis, generic loss of synaptic connectivity all lead to gradual decline of cognitive or motor neuronal function as patients descend into a clinically symptomatic state. Though significant progress has been made in our understanding of neurological disorders in the past decade, it has yet to translate into therapeutic advancements in disease treatment.

We have chosen to focus this review on Alzheimer’s disease (AD) to highlight the main disease modifying mechanisms shared in common with the Huntington’s (HD) and Parkinson’s disease (PD) phenotypes, specifically, the aggregation of amyloid-β (Aβ) phospho-tau (p-tau), mutant huntingtin (mHtt) and α -synuclein (α-syn) proteins, respectively. We highlight a number of approaches used in pre-clinical drug discovery to identify clinical tools. In addition, we describe a number of less explored alternative hypotheses which have demonstrated good (pre)clinical evidence for a potential therapeutic intervention.

In particular, for AD, we will review the main concepts which have driven drug discovery research in the recent past and for each molecular target, we summarize a rationale and available validation data with commentary on relevant chemical matter and structural biology, then discuss advanced pre-clinical and clinical compounds.

Neurodegenerative disorders are known to be multifactorial in nature and current research focus has moved from a ‘one-drug-one-target approach’ to that of drugs which are able to act at various relevant biological targets. These drugs are designed to address more than one etiological target, thereby increasing therapeutic effect and patient compliance and may lower the likelihood of encountering unwanted side-effects. Monoamine oxidase (MAO), nitric oxide synthase (NOS), and acetylcholinesterase (AChE) are enzymes that have long been associated as potential targets for neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. The selective inhibition of the abovementioned enzymes and other relevant CNS targets may provide promising strategies in the development of multifunctional neuroprotective therapeutic agents for the treatment/prevention of neurodegenerative disorders.

Accompanying the gradual rise in the average age of the population of most industrialized countries is a regrettable escalation in individuals afflicted with progressive neurodegenerative disorders, epitomized by Alzheimer's disease (AD). The development of effective new treatment strategies for AD has therefore become one of the most critical challenges in current neuroscience. Cholinesterase inhibitors (ChEIs) remain the primary therapeutic strategy for AD, and act by amplifying residual cholinergic activity, a neurotransmitter system central in cognitive processing that is reported to be depleted in the AD brain. With the recent failure of current drug classes focused towards the molecular events known to underpin AD, including the generation of amyloid-β peptide (Aβ) containing plaques and neurofibrillary tangles (hyperphosphorylated tau). The development of new generation of cholinergic drugs has been accomplished to take advantage of the known modulatory action of the cholinergic system on Aβ, tau production as well as the maintenance synapses, which are known to be lost in AD. Following upon the development of acetylcholinesterase inhibitors (AChE-Is), phenserine, that additionally possessed amyloid precursor protein (APP) synthesis inhibitory actions to lower the generation of Aβ. Selective butyrylcholinesterase inhibitors (BuChE-Is), cymserine analogues, have been developed on the same chemical backbone during further anti-AD research advancement. The above mentioned inhibitors retain actions on APP as well as Aβ and amplify central cholinergic actions without the classical dose-limiting adverse effect profile; therefore, these current BuChE-Is are now moving into AD clinical trials.

Alzheimer's disease (AD) has a progressive neurodegenerative pathology with severe economic and social impact. There is currently no cure, although cholinesterase inhibitors provide effective temporary relief of symptoms in some patients. Nowadays, drug research and development are based on the cholinergic hypothesis that supports the cognition improvement by regulation of the synthesis and release of acetylcholine in the brain. There are only five commercial medicines Donepezil, galantamine, memantine, rivastigmine, tacrine approved for treatment of AD. Natural products have played an important alternative role in the research for new acetylcholinesterase inhibitors, as exemplified through the discovery of galantamine. AD is the dementia associated with aging, which initially targets memory and progressively destroys the functions of the brain, as the neocortex suffers neuronal, synaptic, and dendritic losses. The whole phenomena proliferate due to deposition of amyloid plaques. The goal of the present work is to analyse the search on drugs for the treatment and prevention of AD in the light of Acetyl cholinesterase activity. It is based on systematisation of the data on biochemical and structural similarities in the interaction between physiologically active compounds and their biological targets related to the development of such pathologies.

Although several research strategies have been developed in the last decades, the current therapeutic options for the treatment of Alzheimer’s disease are limited to three acetylcholinesterase inhibitors: galantamine, donepezil and rivastigmine. However, they have only offered a modest improvement in memory and cognitive function. Moreover, these drugs show side effects, and relatively low bioavailability among other problems. These features limit their use in medicine and they lead to a great demand for discovering new acetylcholinesterase inhibitors. In addition to its important role in cholinergic neurotransmission, acetylcholinesterase also participates in other functions related to neuronal development, differentiation, adhesion and amyloid-β processing. Acetylcholinesterase accelerates amyloid-β aggregation and this effect is sensitive to peripheral anionic site blockers. Both features have lead to the development of dual inhibitors of both catalytic active and peripheral anionic sites. These compounds are promising disease-modifying Alzheimer’s disease drug candidates. On the other hand, due to the pathological complexity of Alzheimer’s disease, multifunctional molecules with two or more complementary biological activities may represent an important advance for the treatment of this disease. All these features are described in detail in the present chapter.

Inhibiting the generation of β-amyloid (Aβ) from the amyloid precursor protein (APP) by targeting the protease BACE1, the Alzheimer’s disease β-secretase, is a key strategy for the development of therapeutic compounds aimed at treating Alzheimer’s disease. However, progress in developing biologically active inhibitors has been slow. This is in part because BACE1 possesses a broad and open active site, which cannot be effectively inhibited by small molecules capable of penetrating the bloodbrain barrier. Therefore, there is a great interest in developing modulators of BACE1 activity that are not associated with active site inhibition, rather disrupting the physiological function of the enzyme. This review will discuss the regulation of BACE1 transcriptional expression and modulation of activity by other cellular components, in particular lipids, proteins that interact directly with BACE1, and ubiquitination, as well as BACE1 immunotherapy. This review will also examine the potential of each of these as therapeutic strategies for the treatment of AD.

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is the presence of brain senile plaques made up principally of aggregated amyloid beta (Aβ) peptides. Aβ is produced during the consecutive proteolysis of the transmembrane amyloid precursor protein (APP) by β- and γ-secretases. Genetic and pharmacological manipulations have demonstrated the major β -secretase in AD that makes the initial cleavage required for synthesis of Aβ is the beta-site APP-cleaving enzyme 1 (BACE1). It is therefore very tempting to consider inhibiting BACE1 as a potential AD therapeutic intervention. Here, we review the current knowledge and the molecular and physiological challenges associated with BACE1 inhibition. We also propose alternatives to the direct targeting of CNS BACE1 to prevent AD, as well as methods to measure the therapeutic efficacy of BACE1 inhibition.

A complex disease such as Alzheimer’s requires an arsenal of therapies to help combat and stabilize its advancement. Despite considerable scientific progress, current therapeutic approaches for Alzheimer’s treatment offer only limited and transient benefits to patients. Therefore, in response to the molecular complexity of this disease, a new strategy has recently emerged aimed at simultaneously targeting multiple pathological processes involved in the pathogenesis cascade. β-secretase plays a critical role in β-amyloid formation, a major constituent of amyloid plaques in Alzheimer’s disease (AD) brain and is likely to play a central role in the pathogenesis of this devastating neurodegenerative disorder. Thus, β-secretase is a prime drug target for the therapeutic inhibition of β-amyloid production in AD. It has been clearly established in a number of studies that metal ions are critically involved in the pathogenesis and progression of major neurological diseases (Alzheimer's, Parkinson's). Metal ion chelators have been suggested as potential therapies for diseases involving metal ion imbalance. This chapter summarizes the current therapeutic strategies based on the β-secretase inhibition, metal chelation and their combination to treat AD.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by a progressive loss in memory and cognitive abilities. One of the key pathologic features of AD is the accumulation of beta amyloid (Aβ). Somatostatin has been shown to regulate neuronal neprilysin activity, a key enzyme involved in Aβ catabolism. The actions of somatostatin are mediated through somatostatin receptors 1-5. The somatostatin subtype-4 receptor (sst4) is expressed in key regions of the brain impacted by AD. Thus, sst4 agonists may serve as disease modifying agents (i.e., preventative), enhancing enzymatic activity and decreasing neurotoxic Aβ species within key brain regions of AD patients. This chapter will address the viability of such sst4 agonists within the context of AD therapy, in conjunction with strategies for design, synthesis, and recognition at the macromolecular level.

Neprilysin (NEP) is one of the enzymes in the zinc-metalloendopeptidase family that displays a broad specificity in degrading small bioactive peptides. Crystal structures of seven NEP-inhibitor complexes as well as biochemical characterization of NEP activity have highlighted amino acid interactions that are crucial to the binding of various ligands. Studies also indicate that NEP is one of a select group of metalloenzymes that degrade the amyloid beta peptide (Aβ) in vivo and in situ. The accumulation of neurotoxic Aβ aggregates in the brain appears to be a causative agent in the pathophysiology of Alzheimer’s Disease (AD). For this reason the enzymatic degradation of Aβ has been studied extensively, but little is currently known about the specific interactions underlying NEP degradation of Aβ. Research that pertains to these interactions may lead to critical insights for utilizing NEP inhibition of Aβ accumulation as a safe, beneficial AD therapy.

Alzheimer´s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, cognitive impairment, and at the molecular level, by the presence of neurofibrillary tangles (NFTs). As opposed to degeneration, it is known that some specific regions of the brain contain neural stem cells (NSCs) able to produce neurons during adulthood. Wnt/β-catenin signaling has been described as a key pathway modulating the balance between NSC proliferation and differentiation. Wnt signaling is regulated by glycogen synthase kinase 3 (GSK3) that is constitutively active in the cells, keeps β -catenin phosphorylated on serine and threonine residues, and controls its proteosomal-mediated degradation. This raises the question whether inhibition of GSK3β activity, β -catenin stabilization, and therefore, pharmacological activation of endogenous neurogenesis would be a plausible therapeutic strategy for treating AD patients. In this chapter, we herein review the Wnt/β-catenin signaling and evaluate the strategy of inhibiting GSK3β in the disease.

Tau is a key dynamic regulator of microtubules in neurons. Tau-microtubule binding contributes to axonal stabilization in neurons. Its controlled-physiological weakening allows cell division and microtubule reorganization in fetal state or in mitotic neuronal cells. Tauopathies often show a decreased tau-microtubule binding and the aggregation of tau. The former leads to chronic microtubule-axonal destabilization, the latter preludes to the formation of intra-neuronal, insoluble tau deposits. Tau alternative splicing and post-translational modifications (hyper-phosphorylation, glycosylation, prolylamide bond isomerization, oxidation, etc.) are early events with an impact on tauopathies which may lead to disease-modifying therapeutic interventions. The most prospective therapeutic avenues targeted against these events are presented and critically discussed, selecting a single molecular target of particular relevance. Each target is presented together with its known small molecule modulators. Priority is given to mechanisms, targets and small molecules impacting on more than one tauopathycausing event.

Alzheimer's disease (AD) is the multifarious progressive neuro-degeneration related dementia state among the elders. In fact, number of drugs with different mechanistic prospective were clinically developed and currently under R & D for the symptomatic treatment as well as disease-modifying management of AD. Unluckily, effective and safe delivery of drug in Alzheimer's is restricted due to the presence of biological as well as physiological barriers like blood–brain barrier (BBB), blood– cerebrospinal fluid barrier (BCSFB) and p-glycoproteins. Advancement in nanotechnology based drug delivery systems over the last decade exemplifies effective brain targeting by delivering the drugs at a constant rate that can be extended even up to months. Till recently, various nanomedicines such as polymeric and metallic nanoparticles, SLN, liposomes, micelles dendrimers, nanoemulsions and carbon nano-tube etc have been investigated for effective brain targeting of the drugs particularly in the treatment and diagnosis of AD. Here in this review, we given an account of different barrier in brain drug delivery and possible nanotechnology based strategies that can deliver drugs across the CNS barriers in AD. In addition, we illustrate the typical and new cholinesterase inhibitors for the management of AD, its clinical relevance and the challenges associated with their bioavailable brain delivery. Success of nanomedicines in effective therapeutic targeting in CNS with reference to literatures including the nanomedicines as the novel carrier of cholinesterase inhibitors anti-AD has also covered.