Drug Design and Discovery in Alzheimer’s Disease

1st Edition - June 2, 2015
Editors: Atta-ur Rahman, Muhammad Iqbal Choudhary
Language: English
Paperback ISBN:
9 7 8 - 0 - 1 2 - 8 0 3 9 5 9 - 5
eBook ISBN:
9 7 8 - 0 - 1 2 - 8 0 3 9 6 0 - 1

Drug Design and Discovery in Alzheimer’s Disease includes expert reviews of recent developments in Alzheimer's disease (AD) and neurodegenerative disease research. Originall… Read more

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Drug Design and Discovery in Alzheimer’s Disease includes expert reviews of recent developments in Alzheimer's disease (AD) and neurodegenerative disease research. Originally published by Bentham as Frontiers in Drug Design and Discovery, Volume 6and now distributed by Elsevier, this compilation of the sixteen articles, written by leading global researchers, focuses on key developments in the understanding of the disease at molecular levels, identification and validation of molecular targets, as well as innovative approaches towards drug discovery, development, and delivery. Beginning with an overview of AD pharmacotherapy and existing blockbuster drugs, the reviews cover the potential of both natural and synthetic small molecules; the role of cholinesterases in the on-set and progression of AD and their inhibition; the role of beta-site APP clearing enzyme-1 (BACE-1) in the production of β-amyloid proteins, one of the key reasons of the progression of AD; and other targets identified for AD drug discovery.

Preface
List of Contributors
Chapter 1: Pharmacotherapy of Alzheimer’s Disease: Current State and Future Perspectives
- Abstract
- 1 Alzheimer’s Disease - Historic Overview
- 2 Current Status and Prevalence of AD
- 3 Risk Factors for AD
- 4 Cholinergic Theory
- 5 Cholinesterases
- 6 Current Therapeutic Approaches to AD
- 7 Conclusions
- Acknowledgements
- Conflict of Interest
Chapter 2: Challenges in Designing Therapeutic Agents for Treating Alzheimer’s Disease-from Serendipity to Rationality
- Abstract
- Introduction
- Alzheimer’s Disease (AD)
- Challenges in Designing Alzheimer’s Medicines
- Symptomatic Drugs
- Disease Modifying Drugs (Investigative Approaches)
- Rational Approaches to Design AD Drugs
- Multi-Target-Directed Ligand (MTDL) Design Strategy
- Concluding Remarks & Future Prospects
- Acknowledgements
- Conflict of Interest
- Abbreviations
Chapter 3: Enzyme Inhibitors Involved in the Treatment of Alzheimer’s Disease
- Abstract
- Introduction
- Pathophysiology of Alzheimer Disease
- Overview on Key Enzymes Involved in Alzheimer’s Disease
- Clinically Used Enzymes Inhibitors for Alzheimer’s Disease
- Current Enzyme-Targeted Drug Development for Alzheimer’s Disease
- Conclusions
- Acknowledgements
- Conflict of Interest
- Abbreviations
Chapter 4: Towards Small Molecules as Therapies for Alzheimer’s Disease and Other Neurodegenerative Disorders
- Abstract
- Introduction to Neurodegenerative Diseases
- Alzheimer’s Disease: Etiology and the β-Amyloid Hypothesis
- Bace1 and the β-Amyloid Hypothesis
- The Evolution of Bace1 Inhibitors
- Bace1 Inhibitors: Uncovering “Chemical Truffles” in Pre-Clinical Drug Discovery
- Clinical Inhibitors of β-Secretase
- γ-Secretase and the β-Amyloid Hypothesis
- The Tau Hypothesis
- Alzheimer’s Disease: The Tau Hypothesis and GSK-3
- Future Therapeutic Avenues for AD
- Parkinson’s Disease
- α-Synuclein, a Central Player in PD
- Interplay Between Glucocerebrosidase and α-Synuclein Processing - A New Therapeutic Avenue?
- LRRK2- A Tractable Small Molecule Target for PD?
- Mitochondrial Dysfunction in PD
- Mitochondrial-Targeted Antioxidants in PD
- Mitochondrial Homeostasis Targets
- Iron Chelation Therapies
- Targeting Calcium Homeostasis
- PD: Future Perspectives
- Huntington’s Disease
- HD and Mitochondrial Dysfunction
- The Synergy Between Aggregation and Autophagy
- Transcriptional Regulation
- Other Biological Pathway Deficits
- Perspectives for HD
- Conclusive Remarks
- Acknowledgements
- Conflict of Interest
- Abbreviations
Chapter 5: Multifunctional Enzyme Inhibition for Neuroprotection - A Focus on MAO, NOS, and AChE Inhibitors
- Abstract
- Introduction
- Monoamine Oxidase – Isoforms and Function
- Nitric Oxide Synthase (NOS) – Isoforms and Structure
- Acetylcholinesterase – Structure and Function
- Conclusion and Future Developments
- Acknowledgements
- Conflict of Interest
Chapter 6: Specific Cholinesterase Inhibitors: A Potential Tool to Assist in Management of Alzheimer Disease
- Abstract
- Introduction
- Alzheimer's Disease
- Types of Cholinesterases
- History of AChE
- Distribution of AChE in the Biological Systems
- Biology of AChE
- Functions of AChE
- Binding Sites of AChE
- Molecular Mechanism for AChE Action
- Acetylation Process
- ACh as a Substrate
- Deacetylation Process
- Reversible Inhibitors of AChE
- Irreversible Inhibitors of AChE
- Clinical Aspect of AChE
- Background of BuChE
- BuChE Inhibitors
- Acknowledgements
- Conflict of Interest
Chapter 7: Role of Acetylcholinesterase Inhibitors and Alzheimer Disease
- Abstract
- Introduction
- Synthesis of Acetylcholine (ACh)
- Conclusions
- Acknowledgements
- Conflict of Interest
- Patient Conflict
- Abbreviations
Chapter 8: Research Strategies Developed for the Treatment of Alzheimer’s Disease. Reversible and Pseudo-Irreversible Inhibitors of Acetylcholinesterase: Structure-Activity Relationships and Drug Design
- Abstract
- 1 Introduction
- 2 Acetylcholinesterase
- 3 Inhibitors
- 4 Pseudoirreversible Inhibitors
- 5 Reversible Inhibitors
- Concluding Remarks
- Acknowledgements
- Conflict of Interest
- Abbreviations
Chapter 9: Modulation of BACE1 Activity as a Potential Therapeutic Strategy for Treating Alzheimer’s Disease
- Abstract
- Alzheimer’s Disease – A Background
- BACE1 is the Alzheimer’s β-Secretase
- Targeting BACE1 Therapeutically – Is it a Good Idea?
- Concluding Remarks
- Acknowledgements
- Conflict of Interest
Chapter 10: BACE1 Inhibitors: Attractive Therapeutics for Alzheimer’s Disease
- Abstract
- Introduction
- The β-Secretase Activity and BACE1 in Alzheimer’s
- BACE1 Inhibitor Design
- Human Clinical Trials
- Alternative Strategies
- Conclusions
- Acknowledgements
- Conflict of Interest
Chapter 11: Combining BACE1 Inhibition with Metal Chelation as Possible Therapy for Alzheimer’s Disease
- Abstract
- Introduction
- Alzheimer's Disease
- Beta Secretase
- β-Secretase Inhibitors
- Agents in Clinical Development
- Metal Chelators
- Conclusions
- Acknowledgements
- Conflict of Interest
Chapter 12: Somatostatin Receptor-4 Agonists as Candidates for Treatment of Alzheimer’s Disease
- Abstract
- Introduction
- AD Pathology
- Aβ Degradation and Neprilysin
- Somatostatin and Somatostatin Receptors
- Somatostatin, Neprilysin, and AD Progression
- Targeting sst₄
- Sugar Derivatives
- Thioureas and Related Compounds
- Indole Analogues Developed at Merck
- Non-Peptide Sulfonamides
- 3,4,5-Trisubstituted-1,2,4-Triazoles
- Computational Approaches
- Conclusions
- Acknowledgements
- Conflict of Interest
Chapter 13: Neprilysin Inhibitors Provide Insight into its Specificity and Therapeutic Potential
- Abstract
- The Binding Pocket of Neprilysin
- Computational Modeling
- Amyloid Cascade Hypothesis
- Neprilysin and Aβ Degradation
- Towards Understanding NEP-Aβ Interactions
- Concluding Remarks
- Acknowledgements
- Conflict of Interest
- Abbreviations
Chapter 14: Targeting the GSK3β/β-catenin Signaling to Treat Alzheimer´s Disease: Plausible or Utopic?
- Abstract
- Introduction
- The Scenario: AD Hallmarks
- The Target: GSK3/Β-Catenin Signaling in AD
- The Use of GSK3 Inhibitors as Therapeutical Agents for AD Patients
- Concluding Remarks
- Acknowledgements
- Conflict of Interest
Chapter 15: Targets and Small Molecules Against Tauopathies. Part 1: From Genes to Soluble, Aggregation-Prone Tau Proteins
- Abstract
- Introduction
- CNS Tau Isoforms: To Splice or Not to Splice, that is the Question. …
- Post-Translational Modifications of Tau: The Good, the Bad and the Ugly
- Conclusions
- Acknowledgements
- Conflict of Interest
Chapter 16: Nanomedicine Based Drug Targeting in Alzheimer’s Disease: High Impact of Small Carter
- Abstract
- Introduction
- Role of Acetylcholine Esterase (AChE) in AD
- Anti-AChE Pharmaceuticals
- BLOOD BRAIN BARRIER (BBB): As Obstacle and Therapeutic Target for Anti-AD Drug Development
- NANOMEDICINE: Elucidation for Proficient AD’s Drug Delivery
- NANOMEDICINES IN AD: Desirable Physicochemistry
- Anti-AChE Drug Loaded Nanomedicines
- Conflict of Interest
- Acknowledgements
Index

Atta-ur Rahman

Atta-ur-Rahman, Professor Emeritus, International Center for Chemical and Biological Sciences (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Pakistan, was the Pakistan Federal Minister for Science and Technology (2000-2002), Federal Minister of Education (2002), and Chairman of the Higher Education Commission with the status of a Federal Minister from 2002-2008. He is a Fellow of the Royal Society of London (FRS) and an UNESCO Science Laureate. He is a leading scientist with more than 1283 publications in several fields of organic chemistry.

Affiliations and expertise

Professor Emeritus, International Center for Chemical and Biological Sciences (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Pakistan

Muhammad Iqbal Choudhary

Muhammad Choudhary, PhD, is a Professor of the International Center for Chemical and Biological Sciences, (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Pakistan. He is a member of the Royal Society of Chemistry, London; American Chemical Society; International Union of Pure and Applied Chemistry (IUPAC); American Society of Pharmacology; New York Academy of Sciences; Federation of Asian Chemical Societies (FACS); and he serves on the executive board of the Asian Network of Research on Anti Diabetic Plants (ANRAP). He is a recipient of the National Book Foundation's Prize for Chemistry and the Economic Cooperation Organization (ECO) Award in Education, 2006, given by the President of Azerbaijan. He has published 24 books, more than 570 papers, and 20 patents.

Affiliations and expertise

Professor, International Center for Chemical and Biological Sciences, (H. E. J. Research Institute of Chemistry and Dr. Panjwani Center for Molecular Medicine and Drug Research), University of Karachi, Karachi, Pakistan

Life Sciences

Physical Sciences & Engineering

Social Sciences & Humanities

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