Epigenetic drug discovery for Alzheimer’s disease

Introduction: It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer’s disease (AD).

Areas covered: This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs.

Expert opinion: Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.     

Non human primate models for Alzheimer’s disease-related research and drug discovery

Introduction: Pathophysiological mechanisms underlying Alzheimer’s disease (AD) remain insufficiently documented for the identification of accurate diagnostic markers and purposeful target discovery and development. Nonhuman primates (NHPs) have important translational value given their close phylogenetic relationship to humans and similar developmental paths in (neuro)anatomy, physiology, genetics, and neural functions, as well as cognition, emotion, and social behavior.

Areas covered: This review deals with the past and future role of NHP-based research in AD pathophysiology, diagnosis and drug discovery, and touches upon ethical and legal aspects.

Expert opinion: Aging NHPs are not complete phenocopies of human AD. Conceivably, no other species or experimental model will ever develop the full spectrum of AD-typical alterations. Nevertheless, partial – and even negative – models can increase knowledge of disease mechanisms. Modeling complex brain disorders should not be based on a single model or species. Understanding brain diseases relies on knowledge of healthy brain functioning, and given their close phylogenetic relationship to humans, NHPs serve excellent tools in this respect. NHP-based studies remain essential in the development and validation of radiopharmaceuticals for early diagnostic imaging biomarkers, as well as in the efficacy and safety evaluation of new therapeutic approaches, with active immunization or vaccination approaches as front runners.     

Novel models for Parkinson’s disease and their impact on future drug discovery

Introduction: Parkinson’s disease is a progressive neurodegenerative disease that affects millions of elderly individuals worldwide. Despite intensive efforts dedicated to find a better treatment, the pathogenesis of Parkinson’s Disease remains unknown. In search for a better therapy for the disease, several new in vivo and in vitro models of Parkinson´s disease have been developed in recent times.

Areas covered: The authors provide an outline of the various traditional models of Parkinson´s disease and address those that have been recently generated. They also discuss the utility of these models for the identification of drugs of potential therapeutic value for Parkinson´s Disease patients. From the cell based models and the well-known toxin-based animal models, to the recent genetic models and the increasingly used non-mammalian models, every model is worthwhile in the search for a better Parkinson´s Disease therapy.

Expert opinion: Almost 60 years after its discovery, levodopa is still the gold standard treatment for Parkinson's Disease patients. It seems unlikely that a single model can fully recapitulate the complexity of Parkinson's Disease in the same way it appears improbable that a unique treatment could relieve both the motor and non-motor symptoms of Parkinson's Disease altogether. Therefore treatment will probably require a combination of therapies.     

Pivotal role of nitrogen heterocycles in Alzheimer’s disease drug discovery

Alzheimer’s disease (AD) is a detrimental neurodegenerative disease that progressively worsens with time. Clinical options are limited and only provide symptomatic relief to AD patients. The search for effective anti-AD compounds is ongoing with a few already in Phase III clinical trials, yet to be approved. Heterocycles containing nitrogen are important to biological processes owing to their abundance in nature, their function as subunits of biological molecules and/or macromolecular structures, and their biological activities. The present review discusses previously used strategies, SAR, relevant in vitro and in vivo studies, and success stories of nitrogen-containing heterocyclic compounds in AD drug discovery. Also, we propose strategies for designing and developing novel potent anti-AD small molecules that can be used as treatments for AD.     

Have there been improvements in Alzheimer’s disease drug discovery over the past 5 years?

Introduction: Alzheimer’s disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10–20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective.

Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013–2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (<1% each).

Expert opinion: Unsuccessful outcomes in AD therapeutics are attributed to pathogenic misconceptions, erratic procedures in drug development and inappropriate regulations. Recommendations for the future are as follows: (i) the reconsideration of dominant pathogenic theories, (ii) the identification of reliable biomarkers, (iii) the redefinition of diagnostic criteria, (iv) new guidelines for disease management, (v) the reorientation of drug discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs.     

Idalopirdine as a treatment for Alzheimer’s disease

Introduction: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Pharmacological treatment of AD involves acetylcholinesterase inhibitors (AChEIs) for mild-to-moderate AD and memantine for severe AD. These drugs provide mainly symptomatic short-term benefits without clearly counteracting the progression of the disease. Idalopirdine is an antagonist of the serotonin 6 (5-HT₆) receptor, which is expressed in areas of the CNS involved with memory. Given that there is evidence suggesting that the blockade of 5-HT₆ receptors induces acetylcholine release, it became reasonable to consider that 5-HT₆ antagonism could also be a promising approach for restoring acetylcholine levels in a deteriorated cholinergic system.

Areas covered: This review discusses the history leading to the discovery of idalopirdine, its pharmacokinetics and pharmacodynamics profile and safety issues, together with an overview of clinical trials carried out so far. A literature search was performed with PubMed using the keywords idalopirdine, AD and 5-HT₆ antagonists. The article is also based on information derived from the ClinicalTrials.gov site for clinical trials with idalopirdine.

Expert opinion: Idalopirdine is safe and well tolerated. It could be used as add-on therapy to potentiate the effect of available AChEIs in AD. Nevertheless, results from ongoing Phase III trials are needed to verify whether this drug has a significant clinical effect on cognition in association with AChEIs.     

Diagnostic methods and biomarkers for Alzheimer’s disease

Alzheimer’s disease (AD) is the most frequently occurring and intensively investigated neurodegenerative disorder, which is associated with extracellular senile plaques and intracellular neurofibrillary tangles. In this review, AD related diagnostic strategies and the potential biomarkers of AD will be discussed. Several proteomics methods were developed for disease diagnosis, such as ELISA, MALDI-TOF, SELDI-TOF, and 2 D-electrophoresis. Imaging technologies, such as MRI and PET analyses, are also important, since they could directly show the changes in the brain, associated with dementia progression. MRI technologies might estimate the presence and degree of neurodegeneration by identification and quantification of atrophy. PET could reflect the metabolic changes in the brain by various radioactive molecules (tracers). Along with neuropsycoanalysis of behavioral changes, the progression of dementia can be characterized with biochemical changes in brain metabolisms, in addition to fluctuations in many inflammatory mediators in the cerebral spinal fluid (CSF), blood and in other bodily fluids. These biochemical changes in the brain and other body fluids can be initiated before the appearance of AD symptoms. There is no specific marker for AD along with other dementia, but the combination of different markers may predict the disease progression more accurately. Monitoring the changes in their levels in brain, CSF, blood and body fluids with biomarkers in early disease stages might improve the diagnosis and therapies. Several molecules were established as successful biomarkers for AD diagnosis. Ratio of Abeta42/40 became an important AD marker, which could reflect the disease-associated changes in the blood plasma and CSF. Additional markers were available in blood, such as apolipoprotein E or inflammatory molecules. In CSF, the Abeta42, Tau or phospho-tau could be the most successful biomarker for AD progression. Several new biomarkers and diagnostic approaches were developed for differentiating AD from other forms of dementia. It should be important to predict the AD progression prior to the development of clinical symptoms. Above all, the improvement of above strategies, especially with diverse biomarkers, should support the precise diagnosis of AD, greatly enhancing both AD therapies and preventative measures.     

Progress in acetylcholinesterase inhibitors for Alzheimer’s disease

Current pharmacotherapy of Alzheimer’s disease (AD) involves drugs that are known as acetylcholinesterase inhibitors (AChEIs), which increase the acetylcholine concentration in the brain. Although effective in improving cognitive, behavioural and functional impairments, these drugs are not able to alter disease progression. In this review, the recent patent literature on AChEIs from 2002 to early 2005 will be discussed, focusing attention on the novel analogues of the approved drugs, as well as on the most important AD therapeutic advances. The clinical efficacy of AChEIs will probably be enhanced by their combination with other drugs acting through different pharmacological mechanisms. As the neuronal loss comprises more than the forebrain cholinergic system, the weak effectiveness of AChEIs is not surprising. Besides the ‘cholinergic hypothesis’ approaches, new treatments are emerging based on multipotent compounds able to target the underlying pathogenic mechanisms of AD; these treatments are summarised herein.     

Drug development for Alzheimer’s disease: review

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease, which is considered as one of the most intractable medical problems with heavy social and economic costs. The current drugs for AD, including acetylcholinesterase inhibitors (AChEIs) and memantine, a NMDA receptor antagonist, only temporarily ameliorate cognitive decline, but are unable to stop or reverse the progression of dementia. This paper reviewed the recent advance in AD drug development. The drug discovery programs under clinical trials targeting cholinergic system, α7 nicotinic acetylcholine receptors (nAChRs), N-methyl-d-aspartate receptor (NMDAR), β-secretase, γ-secretase modulators, tau, inflammatory mediators and glucagon-like peptide-1 (GLP-1) were discussed. Though several drug discovery programs are ongoing, the high failure rate is an outstanding issue. Novel techniques and strategies are desperately needed to significantly accelerate this process.     

Developments with multi-target drugs for Alzheimer’s disease: an overview of the current discovery approaches

ABSTRACT

Introduction: Alzheimer’s disease (AD), the most common type of dementia among older adults, is a chronic neurodegenerative pathology that causes a progressive loss of cognitive functioning with a decline of rational skills. It is well known that AD is multifactorial, so there are many different pharmacological targets that can be pursued.

Areas covered: The authors highlight the strategic value of privileged scaffolds in a multi-target lead compound generation against AD, exploring the concept of multi-target design, with a special emphasis on hybrid compounds. Hence, the most promising building blocks for designing and synthesizing hybrid anti-AD drugs are shown, while also presenting the more advanced hybrid compounds.

Expert opinion: The available therapeutic arsenal for AD, designed under the traditional paradigm of ‘one-drug/one target/one-disease’, is based on the inhibition of brain acetylcholinesterase (AChE) to increase acetylcholine (ACh) levels. However, this classical approach has not been sufficiently effective when used to treat any multifactor-depending pathology (cancer, diabetes or AD). The multi-target drug concept has been quickly adopted by medicinal chemists. The basic research developments reported in recent years are a solid foundation that will pave the way for the construction of future AD therapeutics.     

Inflammation and Alzheimer’s disease

Alzheimer’s disease (AD) is the most common form of dementia. It is characterized by extracellular deposition of a specific protein, beta-amyloid peptide fibrils, and is accompanied by extensive loss of neurons in the brains of affected individuals. Although the pathophysiologic mechanism is not fully established, inflammation appears to be involved. Neuroinflammation has been known to play a critical role in the pathogenesis of chronic neurodegenerative disease in general, and in AD in particular. Numerous studies show the presence of a number of markers of inflammation in the AD brain: elevated inflammatory cytokines and chemokines, and accumulation of activated microglia in the damaged regions. Epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs suppresses the progression of AD and delays its onset, suggesting that there is a close correlation between neuroinflammation and AD pathogenesis. The aim of this review is (1) to assess the association between neuroinflammation and AD through discussion of a variety of experimental and clinical studies on AD and (2) to review treatment strategies designed to treat or prevent AD.     

New and emerging drug therapies for Cushing’s disease

Introduction: Cushing’s disease is a rare systemic and disabling disease due to oversecretion of adrenocorticotrophic hormone (ACTH) resulting in excess cortisol levels. Diagnosis and treatment are difficult; despite the availability of various pharmaceutical treatment options, there is an ongoing, unmet need for even more effective treatment.

Areas covered: The present review aims at providing an overview of available drugs and presenting new developments. Focusing on the pituitary as a target, the review covers compounds targeting pituitary cell signaling or cell cycle control such as heat shock protein inhibitors (e.g. silibinin), histone deacetylase inhibitors (trichostatin A, vorinostat), kinase inhibitors (gefitinib, seliciclib), and others (such as triptolide, AT-101). Levoketoconazole and osilodrostat are in clinical testing and inhibit steroidogenesis. Blockade of ACTH receptor binding at the adrenal level is explained as a theoretical drug target. Inhibition of binding of the glucocorticoid receptor in the peripheral tissue plays a minor role due to its lack of biomonitoring options.

Expert opinion: In our opinion, further research and drug development of pituitary-directed targets are necessary. Combination therapies may exert synergistic effects and allow for smaller and better tolerated doses, but more experience and data are needed to guide such treatment schemes.