Recent developments of structure based beta-secretase inhibitors for Alzheimer's disease

The amyloid-beta (Abeta) peptide is the principal components of the senile plaques found in the brains of patients with Alzheimer's disease (AD). The poorly soluble 40-42 amino acid peptide, formed from the cleavage of the Abeta precursor protein (APP) by two proteases, is believed to play a central role in the pathogenesis of AD. Beta-secretase (memapsin 2, BACE1), a membrane-anchored aspartic protease, is responsible for the initial step of APP cleavage leading to the generation of Abeta. Identification and structural determination of beta-secretase have established it to be a primary drug target for AD therapy and stimulated active studies on the inhibitors of this protease. Here we review more recent developments in the design and testing of structure-based beta-secretase inhibitors.     

Recent developments in the drug treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder with an impact on public health which continues to increase with the increasing longevity of the population. The disease is characterised clinically by a progressive loss of cognitive and behavioural function. These deficits are thought to result from decreased cholinergic transmission; therefore, restoring cholinergic function has been the main focus in the development of drugs for AD. Several pharmacological approaches to enhancing cholinergic function have been developed for symptomatic or palliative therapy of AD. Although these strategies have resulted in modest cognitive and behavioural improvements in patients with AD, they do not address the underlying progression of the disease. New strategies will be required to slow, stop or reverse the effects of neurodegeneration in AD. A number of potential therapies are currently under investigation, including estrogen replacement, anti-inflammatory agents, free radical scavengers and antioxidants, and monoamine oxidase-B (MAO-B) inhibitors. The evidence for a protective effect of estrogens or nonsteroidal anti-inflammatory drugs (NSAIDs) is controversial, and largely based on retrospective studies. More controlled prospective studies are needed to definitively demonstrate the benefits of long term estrogen or NSAID use in the prevention of AD. Free radical scavengers/antioxidants such as idebenone, and selective prevention MAO-B inhibitors such as lazabemide are well tolerated, but require additional studies in order to demonstrate preventative effects. In addition, other approaches, such as anti-amyloid treatments that affect beta-amylase secretion, aggregation and toxicity, appear promising; treatments that hinder neurofibrillary tangle construction and nerve growth factor (NGF) induction are in the very early stages of development.     

Acetylcholinesterase inhibitors in the treatment of Alzheimer's disease

Acetylcholinesterase inhibitors have been extensively tested in placebo-controlled studies for use as symptomatic drugs in mild-to-moderate stages of Alzheimer's disease. Published evidence has shown a modest increase in cognitive performance and a stabilisation of functional decline, more evident at higher doses of the respective drugs. It is still unclear as to whether there is a delay in emergence of neuropsychiatric symptoms and in need for nursing home placement. The clinical efficacy of this class of drug will likely be enhanced by combination with other drugs, as well as through non-pharmacologic interventions. Novel trial designs will be required to establish the safety and efficacy of such combinations.     

Recent developments in the pharmacological treatment of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder associated with the loss of dopaminergic neurons in the substantia nigra. The decline of dopamine leads to motor dysfunctions manifested as tremor, rigidity and bradykinesia. The pharmacological treatment of choice for the past 30 years has primarily been the dopamine precursor levodopa. Although it is the most effective treatment available, it is clear that other drugs are needed in order to sustain a therapeutic benefit and to alleviate fluctuations in mobility (i.e., motor fluctuations). Furthermore, there is some evidence that levodopa may hasten the occurrence of motor fluctuations and involuntary movements called dyskinesias. Hence, many clinicians delay the use of levodopa and employ the use of other symptomatic treatments including monoamine oxidase type B (MAO-B) inhibitors and dopamine agonists as first-line therapy in de novo patients. Regardless of treatment, the disease continues to progress as there is still no obvious means of altering disease progression (i.e., no neuroprotective therapy), to restore loss of dopamine (i.e., no restorative therapy) or prevent the disease (i.e. preventative therapy). With disease progression, polypharmacy is common and often employs a combination of antiparkinsonian agents. There have been some key advances in treatment with the advent of MAO-B inhibitors, dopamine agonists and catechol-O-methyltransferase inhibitors; however, the arsenal of drug treatment remains limited. As the mechanism of PD is further elucidated, novel drug treatments will continue to emerge in the areas of preventative, restorative or symptomatic therapy. Despite the purpose of treatment, the ideal pharmacological drug for PD will include the presence of a safe side-effect profile, a simple dosing schedule, the ability to provide symptomatic relief and the potential to alter disease progression. The purpose of this article is to examine upcoming antiparkinsonian drugs in clinical trials based on their pharmacology, safety and efficacy.     

Recent developments in the pharmacological treatment of Crohn's disease

Therapy for Crohn's disease (CD) is rapidly evolving with the emergence of new discoveries in disease pathogenesis. Since the approval of the first biological agent, infliximab, there have been several others that have been studied and are available for use within the context of clinical trials, in CD patients who do not respond to conventional medications or whose disease cannot be maintained in remission with the use of infliximab. The number of available drugs that have focused on the inhibition of TNF is growing. To avoid the injectable route of administering biologicals, several oral agents, such as thalidomide analogues, nonabsorbable antibiotics, such as rifaximin, and specific antibiotics, such as ornidazole, are being studied and considered for patients with CD. Hormonal therapies, such as growth hormone, coherin, medroxyprogesterone acetate and dehydroepiandrosterone, are other novel therapies for CD. Immunomodulators in use in other fields of medicine, including tacrolimus, 6-thioguanine and leflunomide, are being evaluated for the treatment of patients with CD and are also discussed. Several other promising therapies, such as cyclophosphamide, extracorporeal photochemotherapy, stem cell transplantation and the use of porcine whipworm, add to the available therapeutic armamentarium of this life-long remitting and relapsing disease. The future for CD patients is promising with the ever-expanding repertoire of drugs that are being studied.     

Cholinesterase inhibitors for Alzheimer's disease

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease and has become an urgent public health problem in most areas of the world. Substantial progress has been made in understanding the basic neurobiology of AD and, as a result, new drugs for its treatment have become available. Cholinesterase inhibitors (ChEIs), which increase the availability of acetylcholine in central synapses, have become the main approach to symptomatic treatment. ChEIs that have been approved or submitted to the US Food and Drug Administration (FDA) include tacrine, donepezil, metrifonate, rivastigmine and galantamine. In this review we discuss their pharmacology, clinical experience to date with their use and their potential benefits or disadvantages. ChEIs have a significant, although modest, effect on the cognitive status of patients with AD. In addition to their effect on cognition, ChEIs have a positive effect on mood and behaviour. Uncertainty remains about the duration of the benefit because few studies of these compounds beyond one year have been published. Although ChEIs are generally well tolerated, all patients should be followed closely for possible adverse effects. There is no substantial difference in the effectivenes of the various ChEIs, however, they may have different safety profiles. We believe the benefits of their use outweigh the risks and costs and, therefore, ChEls should be considered as primary therapy for patients with mild to moderate AD.     

Cholinesterase inhibitors for the treatment of Alzheimer's disease in the elderly

The treatment of Alzheimer's disease is of increasing importance as the population ages and the number of people with the disease increases. The aetiology of Alzheimer's disease is complex and therefore treatment strategies rely on generalised pathological findings. Cholinesterase inhibitors enhance a generalised deficit of central nervous system acetylcholine and are the first class of agents specifically approved for the treatment of Alzheimer's disease. The clinical efficacy of the different cholinesterase inhibitors is similar; however, differences in pharmacodynamic and pharmacokinetic parameters can influence tolerability and safety in the elderly population. Concomitant disease states, significant drug interactions and the altered kinetics and dynamics seen in elderly patients can also affect treatment outcome. Although cholinesterase inhibitors are not 'curative' for Alzheimer's disease, clinical evidence indicates that these drugs can significantly delay the progress of cognitive impairment. Consequently, they represent a useful treatment for the symptoms of Alzheimer's disease in the elderly.     

The potential for BACE1 inhibitors in the treatment of Alzheimer's disease

Alzheimer's disease (AD) is a debilitating neurodegenerative disease of the elderly characterized by the loss of memory and other cognitive functions. Currently marketed drugs for the treatment of this disease only offer symptomatic relief, and, consequently, there is a large unmet clinical need for disease-modifying therapies for the treatment of AD. Substantial research efforts are focused on inhibiting the proteases involved in the generation of the amyloidogenic beta-amyloid (A beta) peptide. One of these key proteases, beta-secretase, was identified as a novel transmembrane aspartic protease and named BACE1. Due to its pivotal role in A beta production, many pharmaceutical companies are actively pursuing the challenging task of developing BACE1 inhibitors for evaluation in the clinic.     

1,8-Naphthyridine derivatives as cholinesterases inhibitors and cell Ca2+ regulators, a multitarget strategy for Alzheimer's disease

The synthesis and the pharmacological evaluation of 1,8-naphthyridine derivatives and related compounds as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as voltage-dependant Ca(2+) channels (VDCC) modulators of are summarized. These compounds are closely related to the anticholinesterasic tacrine and the well-known Ca(2+)-antagonists 1,4-dihydropyridines. They were obtained from polyfunctionalized 2-amino-3-cyanoheterocycles via Friedlander-type reaction with selected cycloalkanones. Most of the compounds showed moderate inhibitory activity of cholinesterases, with selectivity to the AChE inhibition, and blocked Ca(2+) channels, preferentially the L-subtype, when a 4-aryl-1,4-DHP-like moiety were present in its chemical structure. Taking into account that the regulation of Ca(2+) entry to cells has been described to play a key role in cell death/survival processes, some of them were studied as cytoprotective agentes against different toxic stimuli. Specifically, the 1,8-naphthyridine derivative 30 was described to exert a tiny positive effect on Ca(2+) entry to cells, as single cell, isolated organ, and (45)Ca(2+) uptake experiments showed. This slight "Ca(2+)-promoter" behavior was related to its cytoprotective effect against several toxic stimuli, as Ca(2+)-chelating and antiapoptotic protein Bcl-2 was overexpressed in bovine chromaffin cells preincubated with 30. In fact, the relationship between small elevations of [Ca(2+)](c) and neuroprotection has been deeply studied by our group and others, concluding that a huge blockade of Ca(2+) entry does not have to generate neuroprotection, but the precise regulation, up or down, of such [Ca(2+)] concentrations.     

Recent developments in trans-sialidase inhibitors of Trypanosoma cruzi

Chagas is a lethal chronic disease that currently affects 8–10 million people worldwide, primarily in South and Central America. Trypanosoma cruzi trans-sialidase is an enzyme that is of vital importance for the survival of the parasite due to its key role in the transfer of sialic acid from the host to the parasite surface and it also helps the parasite combat the host’s immune system. This enzyme has no equivalent human enzyme; thus, it has become an interesting target for the development of inhibitors that combat the parasite. In this review, we summarize three classes of inhibitors (acceptor, donor and unrelated) with their inhibition values and their mode of action against this enzyme. Based on molecular docking, molecular dynamics and structure-activity relationship studies, it has been discovered that the molecules with –NH₂, –OH and –COOH groups on an aromatic ring could be used as a scaffold for the development of new and potent trans-sialidase inhibitors due to their key interaction with active enzyme sites. In particular, carboxylic acid derivatives have importance over the sugar moiety due to their ease of synthesis and unique structure-activity relationship.     

Recent developments in the synthesis of acetylcholinesterase inhibitors

The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of a series of pyrano[2,3-b]quinolines (2, 3), [1,8]naphthyridines (5, 6), 4-amino-2,3-diaryl-5,6,7,8-tetrahydrofuro[2,3-b]quinolines (11-13)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]furo[2,3-b]pyridine (14), 4-amino-5,6,7,8-tetrahydro-2,3-diphenylthieno[2,3-b]quinoline (15)/ 4-amino-6,7,8,9-tetrahydro-2,3-diphenyl-5H-cyclohepta[e]thieno[2,3-b]pyridine (16) are described. These compounds are tacrine analogues that have been prepared from readily available polyfunctionalized ethyl [6-amino-5-cyano-4H-pyran]-3-carboxylates (9, 10), ethyl [6-amino-5-cyanopyridine]-3-carboxylates (7, 8), 2-amino-3-cyano-4,5-diarylfurans (17-19) and 2-amino-3-cyano-4,5-diphenylthiophene (20) via Friedl?nder condensation with selected ketones. These compounds are competitive and, in a few cases, non-competitive inhibitors for AChE, the most potent being compound (14), though three-fold less active than tacrine. The BuChE inhibitory activity is only significant in compounds 11 and 14, ten-fold less active than tacrine. Furthermore, the products 12 and 13 are selective and moderate AChE inhibitors.     

半乳糖凝集素-3及其相关抑制剂的研究进展

目的半乳糖凝集素-3(galectin-3)是近年来肿瘤诊断和治疗的新靶点。目前,galectin-3相关抑制剂作为抗肿瘤药物的研究活跃,并取得了一定的研究成果。本文综述了galectin-3在肿瘤细胞凋亡、转移中的作用和近年来galectin-3抑制剂的研究进展。     

Pharmacoeconomics of cholinesterase inhibitors in the treatment of Alzheimer's disease

Cholinesterase inhibitors constitute one of few treatment options available for Alzheimer's disease, the most common cause of dementia. The modest effects and relatively high acquisition costs of these drugs make the health economics of dementia an important subject of study. Simulation models can be used to bring together existing data and make predictions of the long-term cost effectiveness of treatment. Most models have been built around cognitive function as a key parameter based on the observed relationship between cognitive function and costs of care. Patients with more severe disease attain higher total costs of care. Also, these patients have a higher share of formal care costs than do patients with mild disease, who are usually looked after by informal caregivers. The valuation of unpaid care is controversial, and the choice of method may affect results considerably. Another important issue is the measurement of health-related QOL in patients with Alzheimer's disease. The few existing studies have used proxy respondents to elicit utility weights in different disease states; however, this methodology has not been validated. It is likely that the increased drug costs incurred by the use of cholinesterase inhibitors will be offset (at least partly) by savings in other healthcare costs. However, these results should be viewed as preliminary, since we are still awaiting data from long-term follow-up studies. Also, the value of treatment for patients and caregivers in terms of QOL improvements has yet to be established.     

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors

SUMMARY

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD.

Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that

approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine.

In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.     

Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors

Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.