Current Approaches Against Alzheimer's Disease in Clinical Trials

Kuča, Kamil; Soukup, Ondřej; Korábečný, Jan; Nepovimová, Eugenie; Klímová, Blanka; Honegr, Jan; Ramalho, Teodorico C.; França, Tanos C. C.

doi:10.5935/0103-5053.20160048

Cited by 24 publications

(23 citation statements)

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“…Alzheimer's disease has been predominantly studied from the perspective of chemistry and medicine [25][26][27][28][29][30]. Since so much is unknown about AD, some articles seek to predict these unknowns [3][4][5]31,32], while others use artificial intelligence or advanced decision-making methods to address related issues [33][34][35].…”

Section: Related Workmentioning

confidence: 99%

The Business Process Model and Notation Used for the Representation of Alzheimer’s Disease Patients Care Process

Kopecký

Tomášková

2020

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Currently, the number of patients with neurological diseases is increasing, especially those older than 65 suffering from Alzheimer’s disease. This development increases the emphasis on understanding and mapping treatment and care processes, not only for the elderly. Service providers (of both treatment and care) are under general pressure to decrease charges and maintain or improve existing levels of care. This situation is significantly influenced by a comprehensive knowledge of the whole process and its values. This publication therefore aims to describe the fundamental procedural aspects of caring for patients with Alzheimer’s disease, using Business Process Model and Notation (BPMN). It also aims to show the possibilities of using BPMN in the description of treatment and care. Modeling of the business process is more frequently being applied not only by businesses but also by scientists involved in process models. It is used to model medical topics, with approximately 10% of its publications only, and most of these publications deal only with clinical pathways, not with overall treatment and care processes. However, the BPMN model allows the whole process of medical and nonmedical care for patients with Alzheimer’s disease to be described, including the decomposition of partial activities into individual threads and sub-processes or atomic tasks. This paper presents the BPMN modeling and mapping of the specific care path for neurodegenerative patients. The text provides a new perspective on the BPMN modeling of Alzheimer’s disease. The presented model offers the option of expanding treatment cost calculation to simulate the process using graphical tools and languages. The overall view of this system creates a much more complex concept of the system and its surroundings.

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Section: Related Workmentioning

confidence: 99%

The Business Process Model and Notation Used for the Representation of Alzheimer’s Disease Patients Care Process

Kopecký

Tomášková

2020

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“…The PAS site in AChE is the nucleation centre for accumulation of amyloid β and thus, it offers a good target to design drugs aimed at blocking amyloid fibril formation . Clearly, AChE is at the centre of both amyloid and cholinergic hypotheses which in turn suggests that these hypotheses are neither independent and nor mutually exclusive.…”

Section: Introductionmentioning

confidence: 99%

Pyrimidine‐Triazolopyrimidine and Pyrimidine‐Pyridine Hybrids as Potential Acetylcholinesterase Inhibitors for Alzheimer's Disease

et al. 2018

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Acetylcholinesterase (AChE) is a critical enzyme, in Alzheimer's disease (AD) progression and hence has been subjected to intense drug discovery programme. Here, we report synthesis and testing of pyrimidine derivatives in conjugation with triazolopyrimidine based hybrid scaffold of AChE inhibitors for development of new molecules towards the treatment of AD. We used a multipronged approach employing computational, chemical and biological approaches to find the best inhibitor of AChE. Three molecules (10 e, 11 c and 12 b) derived from this scaffold inhibited AChE in nanomolar to micromolar range. Highest activity was shown by 2‐(4‐(6‐(quinolin‐8‐yloxy)pyrimidin‐4‐yl) piperazin‐1‐yl)nicotinonitrile (12 b) which has IC50 value of 36 nM. Inhibitory effect of 12 b was stronger for human AChE in neuronal cell extract compared to eelAChE. This activity is comparable to donepezil (IC50=38nM) which is considered as good standard among AChE inhibitors. The inhibitory activity of 12 b was also in agreement with molecular simulation studies which showed stable interaction of the 12 b with the catalytic active site as well as peripheral anionic site. Molecular simulation studies also indicated stronger interaction of 12 b with rhAChE than TcAChE. This was later confirmed in studies with neuronal cell extract where compound 12 b showed enzyme inhibition at 25 nM. Further this molecule was not found to be toxic or carcinogenic.

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“…Moreover, improvement in the triad of positive symptoms, negative symptoms and cognitive dysfunction in schizophrenia is shown to be mediated by the α 7 receptor in both preclinical and clinical studies [13][14][15] . Several α 7 nAChR agonists (eg, tropisetron [16,17] , GTS-21 [18,19] , TC-5619 (bradanicline) [20][21][22] , EVP-6124 [23] , ABT-126 [24] , AQW051 [25] , Figure 1) have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. FORUM Pharmaceuticals Inc recently completed a phase-III clinical trial of EVP-6124 as an adjunctive pro-cognitive treatment in schizophrenia subjects during chronic, stable, atypical antipsychotic therapy (ClinicalTrials.gov Identifier: NCT01716975).…”

Section: Introductionmentioning

confidence: 99%

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

Shen

Yang

et al. 2016

Acta Pharmacol Sin

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The homomeric α7 nicotinic receptor (α7 nAChR) is widely expressed in the human brain that could be activated to suppress neuroinflammation, oxidative stress and neuropathic pain. Consequently, a number of α7 nAChR agonists have entered clinical trials as anti-Alzheimer's or anti-psychotic therapies. However, high-resolution crystal structure of the full-length α7 receptor is thus far unavailable. Since acetylcholine-binding protein (AChBP) from Lymnaea stagnalis is most closely related to the α-subunit of nAChRs, it has been used as a template for the N-terminal domain of α-subunit of nAChR to study the molecular recognition process of nAChRligand interactions, and to identify ligands with potential nAChR-like activities. Here we report the discovery and optimization of novel acetylcholine-binding protein ligands through screening, structure-activity relationships and structure-based design. We manually screened in-house CNS-biased compound library in vitro and identified compound 1, a piperidine derivative, as an initial hit with moderate binding affinity against AChBP (17.2% inhibition at 100 nmol/L). During the 1st round of optimization, with compound 2 (21.5% inhibition at 100 nmol/L) as the starting point, 13 piperidine derivatives with different aryl substitutions were synthesized and assayed in vitro. No apparent correlation was demonstrated between the binding affinities and the steric or electrostatic effects of aryl substitutions for most compounds, but compound 14 showed a higher affinity (K i =105.6 nmol/L) than nicotine (K i =777 nmol/L). During the 2nd round of optimization, we performed molecular modeling of the putative complex of compound 14 with AChBP, and compared it with the epibatidine-AChBP complex. The results suggested that a different piperidinyl substitution might confer a better fit for epibatidine as the reference compound. Thus, compound 15 was designed and identified as a highly affinitive acetylcholinebinding protein ligand. In this study, through two rounds of optimization, compound 15 (K i =2.8 nmol/L) has been identified as a novel, piperidine-based acetylcholine-binding protein ligand with a high affinity.

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Current Approaches Against Alzheimer's Disease in Clinical Trials

Cited by 24 publications

References 0 publications

The Business Process Model and Notation Used for the Representation of Alzheimer’s Disease Patients Care Process

The Business Process Model and Notation Used for the Representation of Alzheimer’s Disease Patients Care Process

Pyrimidine‐Triazolopyrimidine and Pyrimidine‐Pyridine Hybrids as Potential Acetylcholinesterase Inhibitors for Alzheimer's Disease

Discovery, synthesis, biological evaluation and structure-based optimization of novel piperidine derivatives as acetylcholine-binding protein ligands

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