Trends in CNS Drug Discovery

• Record Nr.: UNINA9911020110203321
• Autore: Doller Dario
• Pubbl/distr/stampa: Newark : , : John Wiley & Sons, Incorporated, , 2025; ©2026
• ISBN: 3-527-84468-6; 3-527-84467-8; 3-527-84469-4
• Edizione: [1st ed.]
• Descrizione fisica: 1 online resource (483 pages)
• Collana: Trends in Drug Discovery Series
• Altri autori (Persone): HodgettsKevin J; FischerJános; KleinChristian; ChildersWayne E; RotellaDavid P
• Lingua di pubblicazione: Inglese
• Formato: Materiale a stampa
• Livello bibliografico: Monografia
• Nota di contenuto: Cover -- Title Page -- Copyright -- Contents -- Series Editors Preface -- Preface -- Chapter 1 CNS Drug Discovery in "The Century of Biology" -- 1.1 Welcome to "The Century of Biology"! -- 1.2 Understanding Brain Health Around the World -- 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 -- References -- Chapter 2 Advances in Disease Modifying Therapies for Parkinson's Disease -- 2.1 Introduction -- 2.2 Parkinson's Disease Pathology -- 2.2.1 Protein Aggregation and Propagation -- 2.2.2 Genetics of Parkinson's Disease -- 2.3 Disease‐Modifying Treatments for Parkinson's Disease -- 2.3.1 α‐Synuclein Targeting -- 2.3.1.1 Immunization -- 2.3.1.2 Reducing α‐Synuclein Expression -- 2.3.1.3 Inhibition of α‐Synuclein Aggregation -- 2.3.1.4 Enhancing Clearance and Degradation of α‐Synuclein -- 2.3.2 Targeting Non‐receptor Tyrosine Kinases c‐Abl -- 2.3.3 Glucocerebrosidase Targeting -- 2.3.4 Leucine‐Rich Repeat Kinase 2 Targeting -- 2.3.5 Targeting Other ; Players -- 2.3.5.1 Targeting Glucagon‐like Peptide‐1 -- 2.3.5.2 Anti‐Apoptotic and Antioxidant Agents -- 2.3.5.3 Myeloperoxidase Inhibitors -- 2.3.5.4 Targeting of α‐Syn Post‐Translational Modifications -- 2.4 Progress and Challenges -- References -- 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 -- 3.4.1 The Receptors -- 3.4.2 The Compounds -- 3.5 Non‐psychedelic Serotonergic Agonists -- 3.6 Atypical Psychedelics -- 3.6.1 κ‐Opioid Receptor (KOR) Agonists Act as Dissociatives.; 3.6.2 N‐Methyl‐D‐Aspartate Receptor (NMDA) Antagonists Are Dissociative Anesthetics -- 3.6.3 γ‐Aminobutyric Acid (GABAA) Receptor Agonists Are Hypnotic Dissociatives -- 3.6.4 Muscarinic Acetylcholine Receptor (mAChR Aka Cholinergic Receptor) Antagonists May Act as Deliriants -- 3.7 Psychoactive Cannabinoids as Atypical Psychedelics -- 3.7.1 What Are Cannabinoids? -- 3.7.2 Cannabinoids as Therapeutics -- 3.7.3 Current and Future Cannabinoid Research -- 3.8 Conclusion -- References -- Chapter 4 Epilepsy and Related Seizure Disorders -- 4.1 Introduction -- 4.1.1 What Is a Seizure? -- 4.1.2 Epilepsy -- 4.1.2.1 Definition -- 4.1.2.2 Classification -- 4.1.3 Medical Management Strategies for Epilepsy -- 4.1.3.1 Present Medical Management in Clinical Practice -- 4.1.3.2 Initiation and Monitoring of ASM -- 4.1.3.3 Patient Response to Anti‐Seizure Medication -- 4.2 Models and Mechanisms of Drug‐Resistant Epilepsy -- 4.2.1 In Vitro Models of Drug‐Resistant Epilepsy -- 4.2.1.1 Low Magnesium Extracellular Concentrations -- 4.2.1.2 4‐Aminopyridine -- 4.2.1.3 Mimicking Additional Components Contributing to Pharmacoresistance -- 4.2.1.4 Patient‐Derived Embryonic and Induced Pluripotent Stem Cells -- 4.2.2 In Vivo Models of Drug‐Resistant Epilepsy -- 4.2.3 Proposed Mechanisms of Drug Resistance -- 4.3 Targets for Drug Development -- 4.3.1 History of Epilepsy Drug Development -- 4.3.2 Mechanisms of Action in Novel Drug Targets under Investigation -- 4.3.2.1 Modulators of Voltage‐Gated Sodium Channels -- 4.3.2.2 Reduction of T‐Type Voltage‐Gated Calcium Channel Activity -- 4.3.2.3 Activators of Voltage‐Gated Potassium Channels -- 4.3.2.4 Modulation of Neurotransmission -- 4.3.2.5 Regulation of Synaptic Vesicle Proteins -- 4.3.2.6 Targeting the Immune System -- 4.3.2.7 Gene Therapy -- 4.3.2.8 Epigenetic Modification -- 4.3.2.9 Modulators of Synaptic Plasticity.; 4.3.2.10 Other -- 4.4 Future Challenges in Epilepsy Drug Development -- Acknowledgments: -- References -- Chapter 5 Strategies for Neuroprotection in Alzheimer's Disease -- 5.1 Introduction -- 5.2 Targeting Pathogenic Protein Aggregation -- 5.2.1 Aβ -- 5.2.1.1 Immunotherapy Against Aβ -- 5.2.1.2 Aβ Cleavage -- 5.2.2 Tau -- 5.2.2.1 Immunotherapy Against Tau -- 5.2.2.2 Gene Therapies -- 5.2.2.3 Modulation of Tau Post‐translation Modifications -- 5.2.2.4 Microtubule Stabilization -- 5.3 Oxidative Stress and Mitochondrial Dysfunction -- 5.4 Neuroinflammation -- 5.5 Protein Processing Pathways -- 5.5.1 Autophagy -- 5.6 Conclusions -- References -- Chapter 6 Rigor in Experimental Design in Nonregulated Preclinical Research in Neuroscience Drug Discovery -- 6.1 Introduction -- 6.2 What Makes Data Robust? -- 6.2.1 Experimental Design Features to Improve Internal Validity -- 6.2.1.1 Randomization -- 6.2.1.2 Blinding -- 6.2.1.3 Exclusion Criteria -- 6.2.1.4 Sex as a Biological Variable (SABV) -- 6.3 Other Types of Validity and Poor Translatability -- 6.4 Threats to Robust Data -- 6.4.1 Underpowered Studies -- 6.4.2 Questionable Research Practices -- 6.4.3 Reporting Bias -- 6.4.4 Lack ; of Preregistration -- 6.4.5 Research Misconduct -- 6.5 Reporting Standards -- 6.6 Animal Welfare -- 6.7 Regulated Versus Nonregulated Nonclinical Studies -- 6.7.1 GLP Studies -- 6.7.2 Non‐GxP Studies -- 6.8 Conclusion -- References -- 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 -- 7.2.1 Biomarker Types and Applications -- 7.2.2 Life Cycle of a Biomarker: From Preclinical Discovery to Clinical Development -- 7.2.2.1 Preclinical Biomarker Discovery -- 7.2.2.2 Biomarkers in Clinical Trials.; 7.2.2.3 The Importance of Validation and Qualification -- 7.3 Biomarkers for Alzheimer's Disease: History and Overview -- 7.3.1 History and Progress in Diagnostic Biomarkers for AD -- 7.3.2 Use of Diagnostic and Potential Surrogate Biomarkers to Facilitate Regulatory Approval for AD -- 7.4 Pharmacodynamic and Candidate Surrogate Biomarkers for AD -- 7.4.1 Core AD Biomarkers: Aβ and Tau -- 7.4.2 The Importance of Biomarkers of Synaptic Health and Function -- 7.4.3 Established Synaptic Biomarkers -- 7.4.4 Exploratory Synaptic Biomarkers -- 7.4.5 Inflammation‐Related Biomarkers -- 7.4.6 Biomarkers of Vascular Dysfunction -- 7.5 Discovering New Biomarkers for AD: An Ongoing Need -- 7.5.1 Identifying New Biomarkers Through Discovery Proteomics -- 7.6 Case Study: Example of Successful Discovery of New Candidate Biomarkers Through Proteomics in the SHINE‐A Clinical Cohort -- 7.6.1 SHINE‐A Use of Biomarkers to Demonstrate Target or Pathway Engagement in a Clinical Trial -- 7.6.2 SHINE‐A Use of Surrogate Biomarkers of Disease Modification -- 7.7 Advancements in Biomarker Discovery and Development for Neurodegenerative Diseases Beyond AD -- 7.8 Conclusions and Future Directions -- References -- Chapter 8 Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) in CNS Drug Discovery -- 8.1 Introduction -- 8.1.1 PET Imaging in Drug Discovery -- 8.1.2 The Early Drug Discovery Situation -- 8.2 PET Imaging in Clinical Drug Development -- 8.2.1 Proof of Distribution (PoD) -- 8.2.2 Proof of Occupancy (PoO) -- 8.2.2.1 Designing Target Occupancy Studies -- 8.2.2.2 Quantifying Target Occupancy -- 8.2.3 Proof of Mechanism (PoM) -- 8.2.3.1 Magnetic Resonance Imaging (MRI) and Hybrid PET/MRI -- 8.3 PET Radioligand Discovery and Development -- 8.3.1 Considerations Before Initiating a CNS PET Radioligand Discovery Project.; 8.3.2 Small Molecule CNS PET Radioligand Design Parameters -- 8.3.3 PET Radioligand Stage‐Gates from Hits to Clinical PET Radioligand -- 8.3.3.1 Hit‐Finding Phase: Radioligand Hits -- 8.3.3.2 Hit‐to‐Lead Phase: Radioligand Leads -- 8.3.3.3 Lead Optimization Phase: Preclinical Radioligand -- 8.3.3.4 Clinical PET Radioligand Candidate -- 8.3.3.5 Clinical PET Radioligand -- 8.3.4 Emerging Application of Immuno‐PET for CNS Imaging -- 8.4 Conclusion -- References -- 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 -- References -- Chapter 10 Discovery of ABBV‐951 ; (VYALEV™/PRODUODOPA®) for Advanced Parkinson's Disease -- 10.1 Introduction -- 10.2 Synthesis of Levodopa and Carbidopa Phosphate Prodrugs -- 10.2.1 Levodopa‐4′‐monophosphate (Foslevodopa) Synthesis -- 10.2.2 Carbidopa‐4′‐monophosphate (Foscarbidopa) Synthesis -- 10.3 Preclinical Characterization -- 10.3.1 Solubility and Stability -- 10.3.2 Bioconversion -- 10.3.3 Preclinical Safety -- 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 -- References.; Chapter 11 Inducers of Targeted Protein Degradation as Drug Candidates for Neurodegenerative Disorders.
• Sommario/riassunto: 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.