摘要
到目前为单靶向疗法在阿尔茨海默病(AD)导致疾病治疗不足。轻微改善仅限于阿尔茨海默病症状患者疾病的早期阶段。许多方法已经开始处理在乙酰胆碱酯酶抑上淀粉样斑块作为首选目标结构制。讨论了各种蛋白激酶促进阿尔茨海默病的发展。所以蛋白激酶是靶点多角度的前景靶向结构。我们确定的小分子蛋白激酶抑制剂的取代的三环benzofuropyridine型显示部分纳摩尔亲和力的阿尔茨海默病相关的糖原合成酶激酶(gsk)3β,细胞外信号调节激酶(ERK)2和C-Jun-N-末端激酶(JNK)3。在各自的激酶抑制作用的取代基效应进行了讨论,这些激酶抑制剂的结合模式的基础上提出了酶的分子对接研究。抑制剂作用在tau蛋白靶向结构显示了以证明酶的条件影响第一个化合物在细胞的研究。
关键词: 多方法,取代基效应、激酶抑制tau蛋白,酶结合,总tau蛋白。
Current Alzheimer Research
Title:Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach
Volume: 13 Issue: 12
Author(s): V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl, A. Hilgeroth
Affiliation:
关键词: 多方法,取代基效应、激酶抑制tau蛋白,酶结合,总tau蛋白。
摘要: So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3β, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
Export Options
About this article
Cite this article as:
V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl, A. Hilgeroth , Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach, Current Alzheimer Research 2016; 13 (12) . https://dx.doi.org/10.2174/1567205013666160615091821
DOI https://dx.doi.org/10.2174/1567205013666160615091821 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Post-Translational Protein Modifications of Rare and Unconventional Types: Implications in Functions and Diseases
Current Medicinal Chemistry Granulocyte Colony-Stimulating Factor Attenuates Blood-Brain Barrier Damage and Improves Cognitive Function in Spontaneously Hypertensive Rats
CNS & Neurological Disorders - Drug Targets Detection of Mild Cognitive Impairment Based on Virtual Reality: A Scoping Review
Current Alzheimer Research Strain Specificity and Drug Resistance in Anti-Prion Therapy
Current Topics in Medicinal Chemistry Non-Globular Structures of Tandem Repeats in Proteins
Protein & Peptide Letters Enhanced Anti-Amyloid Effect of Combined Leptin and Pioglitazone in APP/PS1 Transgenic Mice
Current Alzheimer Research Cholesterol Oxidation Products and Disease: An Emerging Topic of Interest in Medicinal Chemistry
Current Medicinal Chemistry Editorial [“Current Aging Science”: An Important Platform for Reporting Advances in Aging-related Research]
Current Aging Science Effectiveness of a Standardized and Specific Follow-Up in Memory Centers in Patients with Alzheimer’s Disease
Current Alzheimer Research L1CAM Beneficially Inhibits Histone Deacetylase 2 Expression under Conditions of Alzheimer’s Disease
Current Alzheimer Research Editorial [Hot Topic: The Pineal Hormone Melatonin in Health and Disease (Guest Editors: Charanjit Kaur)]
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Guggulsterone for Chemoprevention of Cancer
Current Pharmaceutical Design Conformational Diseases and Structure-Toxicity Relationships: Lessons from Prion-Derived Peptides
Current Protein & Peptide Science Diabetes of the Brain: Computational Approaches and Interventional Strategies
CNS & Neurological Disorders - Drug Targets Expanding the Therapeutic Potential of Statins by Means of Nanotechnology Enabled Drug Delivery Systems
Current Topics in Medicinal Chemistry Predictors of Conversion to Dementia of Probable Alzheimer Type in Patients with Mild Cognitive Impairment
Current Alzheimer Research Neuronal and Glial Cell Abnormality as Predictors of Progression of Diabetic Retinopathy
Current Pharmaceutical Design From the Multifactorial Nature of Alzheimer`s Disease to Multitarget Therapy: The Contribution of the Translational Approach
Current Topics in Medicinal Chemistry Nutrition, Brain Aging, and Alzheimers Disease
Current Nutrition & Food Science Commentary: Neurorestoratology: A Concept and Emerging Discipline in the Treatment of Neurological Disorders
CNS & Neurological Disorders - Drug Targets