Trends in CNS Drug Discovery

Chapter 1: CNS Drug Discovery in "The Century of Biology"

• • 1.1 Welcome to "The Century of Biology"!
• • 1.2 Understanding Brain Health Around theWorld
• • 1.3 Where Are New CNS Drugs Coming from?
• • 1.4 Psychedelics as Potential Therapeutic Drugs
• • 1.5 CNS Drugs Acting at Novel Biological Targets
• • 1.6 Starting with the End in Mind: Defining a CNS Disease
• • 1.7 Where to Go from Here

Chapter 2: Advances in Disease Modifying Therapies for Parkinson's Disease

• • 2.1 Introduction
• • 2.2 Parkinson's Disease Pathology
• • 2.3 Disease-Modifying Treatments for Parkinson's Disease
• • 2.4 Progress and Challenges

Chapter 3: Psychedelics-Inspired Drug Discovery

• • 3.1 Introduction
• • 3.2 What Are Psychedelics and What Makes a Compound, Psychedelic?
• • 3.3 What Is Known about the Therapeutic Mechanism of Action of Psychedelics?
• • 3.4 Typical Psychedelics
• • 3.5 Non-psychedelic Serotonergic Agonists
• • 3.6 Atypical Psychedelics
• • 3.7 Psychoactive Cannabinoids as Atypical Psychedelics
• • 3.8 Conclusion

Chapter 4: Epilepsy and Related Seizure Disorders

• • 4.1 Introduction
• • 4.2 Models and Mechanisms of Drug-Resistant Epilepsy
• • 4.3 Targets for Drug Development
• • 4.4 Future Challenges in Epilepsy Drug Development

Chapter 5: Strategies for Neuroprotection in Alzheimer's Disease

• • 5.1 Introduction
• • 5.2 Targeting Pathogenic Protein Aggregation
• • 5.3 Oxidative Stress and Mitochondrial Dysfunction
• • 5.4 Neuroinflammation
• • 5.5 Protein Processing Pathways
• • 5.6 Conclusions

Chapter 6: Rigor in Experimental Design in Nonregulated Preclinical Research in Neuroscience Drug Discovery

• • 6.1 Introduction
• • 6.2 What Makes Data Robust?
• • 6.3 Other Types of Validity and Poor Translatability
• • 6.4 Threats to Robust Data
• • 6.5 Reporting Standards
• • 6.6 AnimalWelfare
• • 6.7 Regulated Versus Nonregulated Nonclinical Studies
• • 6.8 Conclusion

Chapter 7: Biomarkers in CNS Drug Discovery, Drug Development, and Clinical Implementation

• • 7.1 Introduction
• • 7.2 Biomarkers in Drug Discovery, Development, and Clinical Implementation
• • 7.3 Biomarkers for Alzheimer's Disease: History and Overview
• • 7.4 Pharmacodynamic and Candidate Surrogate Biomarkers for AD
• • 7.5 Discovering New Biomarkers for AD: An Ongoing Need
• • 7.6 Case Study: Example of Successful Discovery of New Candidate Biomarkers Through Proteomics in the SHINE-A Clinical Cohort
• • 7.7 Advancements in Biomarker Discovery and Development for Neurodegenerative Diseases Beyond AD
• • 7.8 Conclusions and Future Directions

Chapter 8: Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) in CNS Drug Discovery

• • 8.1 Introduction
• • 8.2 PET Imaging in Clinical Drug Development
• • 8.3 PET Radioligand Discovery and Development
• • 8.4 Conclusion

Chapter 9: Bioanalytical Strategies to De-risk CNS Drug Discovery for Novel Chemical Modalities

• • 9.1 Introduction
• • 9.2 Permeation of Molecules into the Brain: Key Compartments and Processes
• • 9.3 Key Considerations for Novel Chemical and Biological Constructs
• • 9.4 A Brief History of the Kp,uu Concept and Its Importance for CNS-Focused Drug Design
• • 9.5 Moving Beyond the Rule-of-5 and Newer Territory for CNS Drugs
• • 9.6 Understanding Analytical Errors and Variability in Brain Penetration Measurements
• • 9.7 Potential Bioanalytical Technologies for Novel Modalities
• • 9.8 Bioanalytical Approaches to Account for Brain Concentration and Brain Vascular Volume
• • 9.9 Measuring Target Engagement
• • 9.10 Summary and Conclusions

Chapter 10: Discovery of ABBV-951 (VYALEVTM/PRODUODOPA®) for Advanced Parkinson's Disease

• • 10.1 Introduction
• • 10.2 Synthesis of Levodopa and Carbidopa Phosphate Prodrugs
• • 10.3 Preclinical Characterization
• • 10.4 Clinical First-in-Human and Phase 1 Studies
• • 10.4.1 First-in-human ABBV-951 Study
• • 10.4.2 First in Patient ABBV-951 Study
• • 10.5 Conclusions

Chapter 11: Inducers of Targeted Protein Degradation as Drug Candidates for Neurodegenerative Disorders

• • 11.1 Introduction
• • 11.2 PROTACs for NDs
• • 11.3 Hydrophobic Tagging for the Treatment of NDs
• • 11.4 Approaches Exploiting Lysosomal Degradation for Treatment of NDs
• • 11.5 Other TPD Strategies for the Treatment of NDs
• • 11.6 Availability of TPD Drugs in the CNS
• • 11.7 Summary and Outlook

Chapter 12: Kinase Inhibitors for the Treatment of Brain Diseases

• • 12.1 Introduction
• • 12.2 Kinase Inhibitors for the Treatment of Brain Tumors
• • 12.3 Kinase Inhibitors for the Treatment of Nononcologic Brain Diseases
• • 12.4 Perspectives

Chapter 13: An Academic Laboratory's Approach for Discovering CNS-Active Drug-Like Small Molecules for the Treatment of SMA

• • 13.1 Introduction
• • 13.2 Design of a Library of Riluzole Analogs
• • 13.3 Conclusions

Chapter 14: Medicinal Chemistry "in the System": A CNS Drug Design Narrative Fit for the Century of Biology

• • 14.1 Introduction: Like Biology, Drug Design Is Getting More Complex
• • 14.2 Allosteric Modulation: Transitioning from a Two-Particle to a Three-Particle System
• • 14.3 Orthosteric Drug or Allosteric Drug?
• • 14.4 Examples of Allosteric Modulators Progressing in the Clinic for CNS Indications
• • 14.5 Can Allosteric Functional Effects Be Predicted? The Five Dimensions of Protein Function
• • 14.6 Allosteric Binding Sites: Examples of Allosteric Function
• • 14.7 Beyond Allosterism: Progress Toward Drug Discovery "in a system"
• • 14.8 Non-small Molecule Therapeutics for CNS Disorders
• • 14.9 Summary and a Look Ahead

Chapter 15: The Role of Venture Capital in Drug Discovery

• • 15.1 Introduction
• • 15.2 Sources of Funding: Focusing on the Best Path for Future Success
• • 15.3 Your Company's Value Proposition
• • 15.4 Identifying Key Stakeholders to Ensure Product Adoption
• • 15.5 The Role of Market Definition in Defining the Discovery Opportunity
• • 15.6 Leverage Points in the Buying Process
• • 15.7 Understanding the Competitive Landscape
• • 15.8 The Benefit Ladder
• • 15.9 Developing and Refining the Business Model
• • 15.10 Building the Team to Take You to the Finish Line
• • 15.11 The Current Investment Landscape in Neurology
• • 15.12 A Bright Future for Neuroscience Investment

Chapter 16: Epilog: CNS Drug Discovery – The Years Ahead

• • Acronyms
• • 16.1 The Dual Frontier: AI and the Human Brain in CNS Drug Discovery
• • 16.2 The Rate of CNS Drug Discovery and Reaction Kinetics Theory
• • 16.3 AI Can Discover Novel Drugs (Under the Right Conditions)
• • 16.4 An Example ofWhat AI Cannot Do: Autoantibody Receptor Encephalitis
• • 16.5 The Limitations of Artificial Intelligence in CNS Drug Discovery
• • 16.6 Conclusion: Toward a Brighter Tomorrow
• • References