Abstract
The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimers disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.
Keywords: neuroinflammation, pyridazines, cytokines, drug discovery, glia, alzheimers disease, animal model
Current Alzheimer Research
Title: Validation of the Neuroinflammation Cycle as a Drug Discovery Target Using Integrative Chemical Biology and Lead Compound Development with an Alzheimers Disease-Related Mouse Model
Volume: 2 Issue: 2
Author(s): Wenhui Hu, Hantamalala Ralay Ranaivo, Jeffrey M. Craft, Linda J. Van Eldik and D. Martin Watterson
Affiliation:
Keywords: neuroinflammation, pyridazines, cytokines, drug discovery, glia, alzheimers disease, animal model
Abstract: The neuroinflammation cycle has been proposed as a potential therapeutic target in the development of new approaches to altering Alzheimers disease (AD) progression. However, the efficacy and toxicological profile of compounds that focus only on classical NSAID targets have been disappointing to date. Therefore, we recently initiated an unbiased, integrative chemical biology approach that used a hierarchal set of cell-based screens, followed by efficacy analysis in a new AD-relevant animal model that more closely resembles human pathology endpoints in terms of neuroinflammation and neuronal loss. The prior investigations provided a proof of concept that targeting the neuroinflammation cycle may be a viable drug discovery approach for AD. However, recent informatics analyses of the high attrition rate in drug development have identified the need for starting drug development with lead compounds that are well below cut off values in computed molecular properties in order to facilitate late stage medicinal chemistry refinement to improve in vivo functions. We describe here how we are leveraging our novel, unbiased, integrative chemical biology approach for the rapid discovery of potential lead compounds for AD drug discovery. Specifically, we show that orally bioavailable compounds with the desired physical properties and in vivo functions can be identified in focused synthetic libraries composed of chemical diversifications of the inactive but privileged pyridazine molecular fragment.
Export Options
About this article
Cite this article as:
Hu Wenhui, Ranaivo Ralay Hantamalala, Craft M. Jeffrey, Van Eldik J. Linda and Watterson Martin D., Validation of the Neuroinflammation Cycle as a Drug Discovery Target Using Integrative Chemical Biology and Lead Compound Development with an Alzheimers Disease-Related Mouse Model, Current Alzheimer Research 2005; 2 (2) . https://dx.doi.org/10.2174/1567205053585828
DOI https://dx.doi.org/10.2174/1567205053585828 |
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
-
Engineering Approaches to Develop the Next Generation of Antibodies to Respiratory Targets
Inflammation & Allergy - Drug Targets (Discontinued) Macromolecular Prodrugs Based on Synthetic Polyaminoacids: Drug Delivery and Drug Targeting in Antitumor Therapy
Current Topics in Medicinal Chemistry Nutrigenomics and Its Approaches for Control of Chronic Diseases
Current Biotechnology In the Search of the Vulnerable Plaque: Current Diagnostic Techniques and Future Directions
Vascular Disease Prevention (Discontinued) Insulin Resistance and Postprandial Hyperglycemia the Bad Companions in Natural History of Diabetes: Effects on Health of Vascular Tree
Current Diabetes Reviews The Emerging Roles of Leptin and Ghrelin in Cardiovascular Physiology and Pathophysiology
Current Vascular Pharmacology Endothelial Activation. Sliding Door to Atherosclerosis
Current Pharmaceutical Design Chemical Instability Determines the Biological Action of the Artemisinins
Current Medicinal Chemistry 4Aβ1-15-Derived Monoclonal Antibody Reduces More Aβ Burdens and Neuroinflammation than Homologous Vaccine in APP/PS1 Mice
Current Alzheimer Research Bone Health in Juvenile-Onset Systemic Lupus Erythematosus
Current Rheumatology Reviews Targeting B Cells in SLE: The Experience with Rituximab Treatment (Anti-CD20)
Endocrine, Metabolic & Immune Disorders - Drug Targets Functional and Structural Roles of GPI Moieties in Mammalian Plasma Membranes
Current Organic Chemistry Inflammation as the Common Biological Link Between Depression and Cardiovascular Diseases: Can Carnosine Exert a Protective Role?
Current Medicinal Chemistry The Role of the RhoA/rho-kinase Pathway in Pulmonary Hypertension
Current Drug Discovery Technologies Relevance of Anxiety and Depression in Chronic Obstructive Pulmonary Disease (COPD)
Current Respiratory Medicine Reviews Plumbagin Inhibits Breast Tumor Bone Metastasis and Osteolysis by Modulating the Tumor-Bone Microenvironment
Current Molecular Medicine Editorial: Drug Targets and Biomarkers for Obstetric/Gynecologic/Reproductive Diseases
Current Drug Targets Leukocyte Adhesion: A Suitable Target for Anti-Inflammatory Drugs
Current Pharmaceutical Design How to Treat Osteoarthritis in Obese Patients?
Current Rheumatology Reviews Nitric Oxide: Cancer Target or Anticancer Agent?
Current Cancer Drug Targets