Trends in CNS Drug Discovery

Dario Doller, PhD, has over 30 years of experience in pharmaceutical research, contributing to numerous clinical compounds and a marketed drug. He has authored over 100 articles and patents and is Chief Scientific Officer at Modulate Bio.Kevin J. Hodgetts, PhD, is Associate Professor of Neurology at Harvard Medical School and Head of Medicinal Chemistry and Director of the Lab for Drug Discovery in Neuroscience (LDDN) at Brigham and Women’s Hospital.

• Series Editors Preface xiiiPreface xv1 CNS Drug Discovery in "The Century of Biology" 1Dario Doller1.1 Welcome to "The Century of Biology"! 11.2 Understanding Brain Health Around theWorld 21.3 Where Are New CNS Drugs Coming from? 31.4 Psychedelics as Potential Therapeutic Drugs 51.5 CNS Drugs Acting at Novel Biological Targets 81.6 Starting with the End in Mind: Defining a CNS Disease 91.7 Where to Go from Here 112 Advances in Disease Modifying Therapies for Parkinson's Disease 17Kambiz Hassanzadeh and M. Maral Mouradian2.1 Introduction 182.2 Parkinson's Disease Pathology 182.3 Disease-Modifying Treatments for Parkinson's Disease 212.4 Progress and Challenges 443 Psychedelics-Inspired Drug Discovery 67Alan Gibbs and Tanweer Khan3.1 Introduction 683.2 What Are Psychedelics and What Makes a Compound, Psychedelic? 693.3 What Is Known about the Therapeutic Mechanism of Action of Psychedelics? 693.4 Typical Psychedelics 703.5 Non-psychedelic Serotonergic Agonists 753.6 Atypical Psychedelics 773.7 Psychoactive Cannabinoids as Atypical Psychedelics 803.8 Conclusion 824 Epilepsy and Related Seizure Disorders 91Jovanna A. Tracz and Alberto E. Musto4.1 Introduction 924.2 Models and Mechanisms of Drug-Resistant Epilepsy 984.3 Targets for Drug Development 1004.4 Future Challenges in Epilepsy Drug Development 1075 Strategies for Neuroprotection in Alzheimer's Disease 117Hilary Grosso Jasutkar5.1 Introduction 1185.2 Targeting Pathogenic Protein Aggregation 1205.3 Oxidative Stress and Mitochondrial Dysfunction 1285.4 Neuroinflammation 1305.5 Protein Processing Pathways 1305.6 Conclusions 1326 Rigor in Experimental Design in Nonregulated Preclinical Research in Neuroscience Drug Discovery 141Sara Steele, Anton Bespalov, and Els Dequeker6.1 Introduction 1416.2 What Makes Data Robust? 1426.3 Other Types of Validity and Poor Translatability 1456.4 Threats to Robust Data 1476.5 Reporting Standards 1516.6 AnimalWelfare 1546.7 Regulated Versus Nonregulated Nonclinical Studies 1546.8 Conclusion 1557 Biomarkers in CNS Drug Discovery, Drug Development, and Clinical Implementation 161Valentina Di Caro, Claire Williams, Hilary A. North, and Mary E. Hamby7.1 Introduction 1627.2 Biomarkers in Drug Discovery, Development, and Clinical Implementation 1647.3 Biomarkers for Alzheimer's Disease: History and Overview 1727.4 Pharmacodynamic and Candidate Surrogate Biomarkers for AD 1747.5 Discovering New Biomarkers for AD: An Ongoing Need 1827.6 Case Study: Example of Successful Discovery of New Candidate Biomarkers Through Proteomics in the SHINE-A Clinical Cohort 1847.7 Advancements in Biomarker Discovery and Development for Neurodegenerative Diseases Beyond AD 1867.8 Conclusions and Future Directions 1898 Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) in CNS Drug Discovery 199Benny Bang-Andersen and Hanne Demant Garling8.1 Introduction 2008.2 PET Imaging in Clinical Drug Development 2018.3 PET Radioligand Discovery and Development 2088.4 Conclusion 2189 Bioanalytical Strategies to De-risk CNS Drug Discovery for Novel Chemical Modalities 229Scott G. Summerfield, David A. Fairman, and James W.T. Yates9.1 Introduction 2309.2 Permeation of Molecules into the Brain: Key Compartments and Processes 2309.3 Key Considerations for Novel Chemical and Biological Constructs 2349.4 A Brief History of the Kp,uu Concept and Its Importance for CNS-Focused Drug Design 2389.5 Moving Beyond the Rule-of-5 and Newer Territory for CNS Drugs 2399.6 Understanding Analytical Errors and Variability in Brain Penetration Measurements 2419.7 Potential Bioanalytical Technologies for Novel Modalities 2439.8 Bioanalytical Approaches to Account for Brain Concentration and Brain Vascular Volume 2449.9 Measuring Target Engagement 2469.10 Summary and Conclusions 24710 Discovery of ABBV-951 (VYALEVTM/PRODUODOPA®) for Advanced Parkinson's Disease 255Eric A. Voight, Matthew R. Rosebraugh, and Philip R. Kym10.1 Introduction 25510.2 Synthesis of Levodopa and Carbidopa Phosphate Prodrugs 25710.3 Preclinical Characterization 26010.4 Clinical First-in-Human and Phase 1 Studies 26310.4.1 First-in-human ABBV-951 Study 26310.4.2 First in Patient ABBV-951 Study 26610.5 Conclusions 26811 Inducers of Targeted Protein Degradation as Drug Candidates for Neurodegenerative Disorders 273Shusuke Tomoshige and Minoru Ishikawa11.1 Introduction 27411.2 PROTACs for NDs 28111.3 Hydrophobic Tagging for the Treatment of NDs 29011.4 Approaches Exploiting Lysosomal Degradation for Treatment of NDs 29111.5 Other TPD Strategies for the Treatment of NDs 29511.6 Availability of TPD Drugs in the CNS 29611.7 Summary and Outlook 30312 Kinase Inhibitors for the Treatment of Brain Diseases 311Chenzhong Liao, Qin Wang, and Zhouling Xie12.1 Introduction 31212.2 Kinase Inhibitors for the Treatment of Brain Tumors 31612.3 Kinase Inhibitors for the Treatment of Nononcologic Brain Diseases 33312.4 Perspectives 34213 An Academic Laboratory's Approach for Discovering CNS-Active Drug-Like Small Molecules for the Treatment of SMA 353Kevin J. Hodgetts, Anne Rietz, and Elliot J. Androphy13.1 Introduction 35313.2 Design of a Library of Riluzole Analogs 36013.3 Conclusions 37114 Medicinal Chemistry "in the System": A CNS Drug Design Narrative Fit for the Century of Biology 377Dario Doller14.1 Introduction: Like Biology, Drug Design Is Getting More Complex 37714.2 Allosteric Modulation: Transitioning from a Two-Particle to a Three-Particle System 37814.3 Orthosteric Drug or Allosteric Drug? 38014.4 Examples of Allosteric Modulators Progressing in the Clinic for CNS Indications 38514.5 Can Allosteric Functional Effects Be Predicted? The Five Dimensions of Protein Function 39114.6 Allosteric Binding Sites: Examples of Allosteric Function 39414.7 Beyond Allosterism: Progress Toward Drug Discovery "in a system" 39614.8 Non-small Molecule Therapeutics for CNS Disorders 39914.9 Summary and a Look Ahead 40215 The Role of Venture Capital in Drug Discovery 411Arthur J. Hiller15.1 Introduction 41115.2 Sources of Funding: Focusing on the Best Path for Future Success 41415.3 Your Company's Value Proposition 41815.4 Identifying Key Stakeholders to Ensure Product Adoption 41915.5 The Role of Market Definition in Defining the Discovery Opportunity 41915.6 Leverage Points in the Buying Process 42215.7 Understanding the Competitive Landscape 42315.8 The Benefit Ladder 42515.9 Developing and Refining the Business Model 42715.10 Building the Team to Take You to the Finish Line 42715.11 The Current Investment Landscape in Neurology 42815.12 A Bright Future for Neuroscience Investment 43216 Epilog: CNS Drug Discovery – The Years Ahead 439Dario DollerAcronyms 43916.1 The Dual Frontier: AI and the Human Brain in CNS Drug Discovery 43916.2 The Rate of CNS Drug Discovery and Reaction Kinetics Theory 44116.3 AI Can Discover Novel Drugs (Under the Right Conditions) 44516.4 An Example ofWhat AI Cannot Do: Autoantibody Receptor Encephalitis 44716.5 The Limitations of Artificial Intelligence in CNS Drug Discovery 44916.6 Conclusion: Toward a Brighter Tomorrow 451References 451Index 455