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Full Description
Provides insights into the drug discovery innovations that are shaping future CNS therapies
In the vast field of neuroscience, drug discovery targeting the central nervous system (CNS) presents both extraordinary opportunities and complex challenges. Disorders such as Alzheimer's disease, schizophrenia, and epilepsy affect millions worldwide, demanding innovative therapeutic strategies. Yet understanding brain processes and overcoming the blood-brain barrier continue to pose significant hurdles for researchers and developers alike.
Trends in CNS Drug Discovery offers a comprehensive overview of the methodologies, successes, and challenges shaping this critical area of pharmaceutical research. Covering a wide range of key areas, from current therapeutic paradigms to emerging technologies, this state-of-the-art volume brings together expertise from leading scientists and drug developers who address the role of cannabinoids and psychedelics in advancing CNS therapeutics, discuss emerging modalities such as protein degraders and allosteric modulators, examine funding strategies and academic-industrial collaborations, highlight advancements in brain-penetrating cancer treatments and other high-impact areas, and more.
Explores cutting-edge methodologies, including biomarkers, animal models, and brain imaging for CNS drug discovery
Reviews innovative therapies such as combination drugs and prodrugs for improved treatment outcomes
Analyzes challenges in targeting diseases including Alzheimer's and schizophrenia with novel therapeutic strategies
Includes real-world case studies demonstrating achievements and lessons in CNS drug development
A critical reference for academic researchers and industry professionals in medicinal chemistry, pharmaceutical research, and neurobiology, Trends in CNS Drug Discovery is also an ideal resource for graduate-level courses in neuroscience or pharmaceutical sciences.
Contents
Series Editors Preface xiii
Preface xv
1 CNS Drug Discovery in "The Century of Biology" 1
Dario Doller
1.1 Welcome to "The Century of Biology"! 1
1.2 Understanding Brain Health Around theWorld 2
1.3 Where Are New CNS Drugs Coming from? 3
1.4 Psychedelics as Potential Therapeutic Drugs 5
1.5 CNS Drugs Acting at Novel Biological Targets 8
1.6 Starting with the End in Mind: Defining a CNS Disease 9
1.7 Where to Go from Here 11
2 Advances in Disease Modifying Therapies for Parkinson's Disease 17
Kambiz Hassanzadeh and M. Maral Mouradian
2.1 Introduction 18
2.2 Parkinson's Disease Pathology 18
2.3 Disease-Modifying Treatments for Parkinson's Disease 21
2.4 Progress and Challenges 44
3 Psychedelics-Inspired Drug Discovery 67
Alan Gibbs and Tanweer Khan
3.1 Introduction 68
3.2 What Are Psychedelics and What Makes a Compound, Psychedelic? 69
3.3 What Is Known about the Therapeutic Mechanism of Action of Psychedelics? 69
3.4 Typical Psychedelics 70
3.5 Non-psychedelic Serotonergic Agonists 75
3.6 Atypical Psychedelics 77
3.7 Psychoactive Cannabinoids as Atypical Psychedelics 80
3.8 Conclusion 82
4 Epilepsy and Related Seizure Disorders 91
Jovanna A. Tracz and Alberto E. Musto
4.1 Introduction 92
4.2 Models and Mechanisms of Drug-Resistant Epilepsy 98
4.3 Targets for Drug Development 100
4.4 Future Challenges in Epilepsy Drug Development 107
5 Strategies for Neuroprotection in Alzheimer's Disease 117
Hilary Grosso Jasutkar
5.1 Introduction 118
5.2 Targeting Pathogenic Protein Aggregation 120
5.3 Oxidative Stress and Mitochondrial Dysfunction 128
5.4 Neuroinflammation 130
5.5 Protein Processing Pathways 130
5.6 Conclusions 132
6 Rigor in Experimental Design in Nonregulated Preclinical Research in Neuroscience Drug Discovery 141
Sara Steele, Anton Bespalov, and Els Dequeker
6.1 Introduction 141
6.2 What Makes Data Robust? 142
6.3 Other Types of Validity and Poor Translatability 145
6.4 Threats to Robust Data 147
6.5 Reporting Standards 151
6.6 AnimalWelfare 154
6.7 Regulated Versus Nonregulated Nonclinical Studies 154
6.8 Conclusion 155
7 Biomarkers in CNS Drug Discovery, Drug Development, and Clinical Implementation 161
Valentina Di Caro, Claire Williams, Hilary A. North, and Mary E. Hamby
7.1 Introduction 162
7.2 Biomarkers in Drug Discovery, Development, and Clinical Implementation 164
7.3 Biomarkers for Alzheimer's Disease: History and Overview 172
7.4 Pharmacodynamic and Candidate Surrogate Biomarkers for AD 174
7.5 Discovering New Biomarkers for AD: An Ongoing Need 182
7.6 Case Study: Example of Successful Discovery of New Candidate Biomarkers Through Proteomics in the SHINE-A Clinical Cohort 184
7.7 Advancements in Biomarker Discovery and Development for Neurodegenerative Diseases Beyond AD 186
7.8 Conclusions and Future Directions 189
8 Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) in CNS Drug Discovery 199
Benny Bang-Andersen and Hanne Demant Garling
8.1 Introduction 200
8.2 PET Imaging in Clinical Drug Development 201
8.3 PET Radioligand Discovery and Development 208
8.4 Conclusion 218
9 Bioanalytical Strategies to De-risk CNS Drug Discovery for Novel Chemical Modalities 229
Scott G. Summerfield, David A. Fairman, and James W.T. Yates
9.1 Introduction 230
9.2 Permeation of Molecules into the Brain: Key Compartments and Processes 230
9.3 Key Considerations for Novel Chemical and Biological Constructs 234
9.4 A Brief History of the Kp,uu Concept and Its Importance for CNS-Focused Drug Design 238
9.5 Moving Beyond the Rule-of-5 and Newer Territory for CNS Drugs 239
9.6 Understanding Analytical Errors and Variability in Brain Penetration Measurements 241
9.7 Potential Bioanalytical Technologies for Novel Modalities 243
9.8 Bioanalytical Approaches to Account for Brain Concentration and Brain Vascular Volume 244
9.9 Measuring Target Engagement 246
9.10 Summary and Conclusions 247
10 Discovery of ABBV-951 (VYALEVTM/PRODUODOPA®) for Advanced Parkinson's Disease 255
Eric A. Voight, Matthew R. Rosebraugh, and Philip R. Kym
10.1 Introduction 255
10.2 Synthesis of Levodopa and Carbidopa Phosphate Prodrugs 257
10.3 Preclinical Characterization 260
10.4 Clinical First-in-Human and Phase 1 Studies 263
10.4.1 First-in-human ABBV-951 Study 263
10.4.2 First in Patient ABBV-951 Study 266
10.5 Conclusions 268
11 Inducers of Targeted Protein Degradation as Drug Candidates for Neurodegenerative Disorders 273
Shusuke Tomoshige and Minoru Ishikawa
11.1 Introduction 274
11.2 PROTACs for NDs 281
11.3 Hydrophobic Tagging for the Treatment of NDs 290
11.4 Approaches Exploiting Lysosomal Degradation for Treatment of NDs 291
11.5 Other TPD Strategies for the Treatment of NDs 295
11.6 Availability of TPD Drugs in the CNS 296
11.7 Summary and Outlook 303
12 Kinase Inhibitors for the Treatment of Brain Diseases 311
Chenzhong Liao, Qin Wang, and Zhouling Xie
12.1 Introduction 312
12.2 Kinase Inhibitors for the Treatment of Brain Tumors 316
12.3 Kinase Inhibitors for the Treatment of Nononcologic Brain Diseases 333
12.4 Perspectives 342
13 An Academic Laboratory's Approach for Discovering CNS-Active Drug-Like Small Molecules for the Treatment of SMA 353
Kevin J. Hodgetts, Anne Rietz, and Elliot J. Androphy
13.1 Introduction 353
13.2 Design of a Library of Riluzole Analogs 360
13.3 Conclusions 371
14 Medicinal Chemistry "in the System": A CNS Drug Design Narrative Fit for the Century of Biology 377
Dario Doller
14.1 Introduction: Like Biology, Drug Design Is Getting More Complex 377
14.2 Allosteric Modulation: Transitioning from a Two-Particle to a Three-Particle System 378
14.3 Orthosteric Drug or Allosteric Drug? 380
14.4 Examples of Allosteric Modulators Progressing in the Clinic for CNS Indications 385
14.5 Can Allosteric Functional Effects Be Predicted? The Five Dimensions of Protein Function 391
14.6 Allosteric Binding Sites: Examples of Allosteric Function 394
14.7 Beyond Allosterism: Progress Toward Drug Discovery "in a system" 396
14.8 Non-small Molecule Therapeutics for CNS Disorders 399
14.9 Summary and a Look Ahead 402
15 The Role of Venture Capital in Drug Discovery 411
Arthur J. Hiller
15.1 Introduction 411
15.2 Sources of Funding: Focusing on the Best Path for Future Success 414
15.3 Your Company's Value Proposition 418
15.4 Identifying Key Stakeholders to Ensure Product Adoption 419
15.5 The Role of Market Definition in Defining the Discovery Opportunity 419
15.6 Leverage Points in the Buying Process 422
15.7 Understanding the Competitive Landscape 423
15.8 The Benefit Ladder 425
15.9 Developing and Refining the Business Model 427
15.10 Building the Team to Take You to the Finish Line 427
15.11 The Current Investment Landscape in Neurology 428
15.12 A Bright Future for Neuroscience Investment 432
16 Epilog: CNS Drug Discovery - The Years Ahead 439
Dario Doller
Acronyms 439
16.1 The Dual Frontier: AI and the Human Brain in CNS Drug Discovery 439
16.2 The Rate of CNS Drug Discovery and Reaction Kinetics Theory 441
16.3 AI Can Discover Novel Drugs (Under the Right Conditions) 445
16.4 An Example ofWhat AI Cannot Do: Autoantibody Receptor Encephalitis 447
16.5 The Limitations of Artificial Intelligence in CNS Drug Discovery 449
16.6 Conclusion: Toward a Brighter Tomorrow 451
References 451
Index 455
