Designing Multi-Target Drugs

Transcription

1 - ' : Designing Multi-Target Drugs Edited by J. Richard Morphy Stirling, UK* C. John Harris Eynsford, Kent, UK Current address: Lilly Research Centre, Research Centre. Surrey GU20 9PH. UK. Publishing

2 Contents Chapter 1 Simple Drugs Do Not Cure Complex Diseases: The Need for Multi-Targeted Drugs 1 Jorrit J. Introduction 1 The Need for Better and Safer Drugs Cancer 2 Rheumatoid Arthritis Control of Complex Biological Systems Safety of Multi-Targeted Drugs Toxicity Off-Target Toxicity Toxicity Concluding Remarks Acknowledgements 9 References 9 Chapter 2 Clinical Need and Rationale for Multi-Target Drugs in Psychiatry 14 Mohammed Shahid 2.1 Introduction Clinical Need Rationale For Multi-Target Agents: Multifunctional Pharmacology and Multi-Therapeutic Application 2.4 New Introductions Agomelatine Vilazodone Asenapine 22 RSC Drug Discovery Series No. 21 Designing Multi-Target Drugs Edited by J. Richard Morphy and C. John Harris Royal Society of Chemistry 2012 Published by the Royal Society of Chemistry,

3 xx Contents Lurasidone 24 S Iloperidone Emerging promising Compounds in Development 24 Cariprazine Lu AA21004 and Zicronapine LY Summary and Future Perspectives 27 Acknowledgements 28 References 28 Chapter 3 Drug Molecules and Biology: Network and Systems Aspects 32 Malcolm P. Young, Steven and Alan V. Whitmore 3.1 Biological Robustness and Therapeutic Discovery Biological Networks and Their Properties Multiple Interventions: Expect the Unexpected Effective Drugs and Multiple Interventions in Networks Drug Discovery problems in Light of Network Science Network Exploiting Advances in Chemical Biology and Network Science Prospects for Multi-Target Drug Discovery in Light of Network Science 46 Glossary 46 References 48 Chapter 4 Approaches to Target 50 Elisabet and Michael J. Keiser Introduction Approaches 51 Representing Ligands for Similarity Calculations 51 Organizing Biological Targets by their Ligands 52 Profiling Applications Target Identification 59 Safety and Target-Specific Toxicity 60 Applicability 61 References

4 Contents Chapter 5 Designing Multi-Target Drugs: In Vitro Panel Screening - Biological Fingerprinting 66 Jonathan S. Mason 5.1 Introduction: Biological Fingerprints - A Biological View of Compounds The Cerep Database Profiling Concepts and Practice 5.4 Profiling of Drugs: The Multi-Target/ Polypharmacology of Drugs 72 Profiling of Project Compounds 73 Choosing the Best Hit or Lead Compound and Differentiation Profiling of Tool Compounds: Target Validation Selectivity and the Use of the Broad In Vitro Biological Profile to Predict In Vivo Effects and Safety Issues of Attrited Compounds Profiling and Clustering of Compounds: In Silico Descriptors and Similarity Issues In Vitro Panel Screening: The Future 82 References 82 xxi Chapter 6 Phenotypic and In Vivo Screening: Lead Discovery and Drug Repurposing 86 Christopher A. Lipinski Changes in Screening Philosophy Phenotypic Screening: Advantages, Disadvantages, Ligand Matching and MTDD Drug Repurposing: Leveraging Signaling Network Activities 90 References 92 Chapter 7 Target/s Identification Approaches - Experimental Biological Approaches 94 Giulio Kilian Huber and Georg Winter Introduction Yeast Genomic Assays (HIP) Homozygous Profiling (HOP)/Haploid Deletion Chemical Genetic Profiling 97

5 xxii Chapter 8 Contents 7.3 Genomic Assays in Mammalian Cells Comparative Gene Expression Profiling RNA Interference-Based Screens Proteomic Approaches Compound-Centred Chemical Proteomics (CCCP) Kinobeads Activity-Based Protein Profiling (ABPP) Global Phosphoproteomics Lysine Acetylation Profiling Drug Affinity Responsive Target Stability (DARTS) Other Methods Yeast Three-Hybrid (Y3H) Protein Microarrays Conclusions 107 References 107 Historical Strategies for Lead Generation J. Richard Morphy 8.1 Introduction 8.2 Historical Approaches Framework Combination Screening Comparing Lead Generation Approaches Emerging Approaches Fragment Approach Virtual Screening Structure Guided Approaches Natural Products Chemical Biology 8.5 Factors Influencing the Feasibility of MTDD Summary 126 References Chapter 9 In Silico Lead Generation Approaches in Multi-Target Drug Discovery Xiaohou Ma and Chen 9.1 Introduction to In Silico Screening Methods Molecular Docking Pharmacophores QSAR 132 Machine Learning Methods

6 Application In Silico Screening to MTDD 133 Perspectives References Chapter 10 The Challenges of Multi-Target Lead Optimization 141 Richard Morphy 10.1 Introduction 141 Optimization of the Activity Profile Wider Selectivity Physicochemical Properties Summary 153 References Chapter 11 Combination Agents Versus Multi-Targeted Agents - Pros and Cons Jose G. Monzon and Janet Dancey Introduction 155 Principles of Combination Chemotherapy for the Treatment of Cancer Principle #1: All Drugs Must be Active as Single Agents Principle #2: Drugs Should be Chosen for Non-Overlapping Toxicity Principle #3: Drugs Should be Chosen for Different Synergistic Mechanisms of Action Principle #4: Drugs Should be Chosen That Have Different Mechanisms or Patterns of Resistance Principle #5: Drugs Should be Administered at the Optimum Dose and Schedule Comparison of Combinations of Single Target Drugs Versus Multi-Targeted Agents - The Pros and Cons of Each Approach 11.4 Defining which Targeted Agents to Combine 165 Examples and Rationale Behind Combination MTTs Preclinical Evaluation of Combinations 169 Factors that Limit the Applicability of Vitro Studies 170 Factors that Limit the Applicability of In Vivo Studies 171

7 xxiv Contents Challenges in the Clinical Development of Drug Combinations Future Directions 174 References 175 Chapter 12 The Discovery of Lapatinib 181 Karen E. Lackey 12.1 Introduction to Inhibition of Kinases for Cancer Therapeutics Developing a Lead Series for Dual Kinase Inhibition Performing Multi-Dimensional Data Analysis for Achieving the Target Profile Optimizing Drug Properties whilst Retaining the Target Profile Pyridopyrimidines Ether Linked 4-Anilinoquinazolines Linked 4-Anilinoquinazolines Alkynylpyrimidine Series 197 Understanding the Mode of Inhibition That Makes Lapatinib Analogs Effective Conclusion 200 Acknowledgements 203 References 204 Chapter 13 Identification and Optimization of Dual Inhibitors 206 Andreas Karlsson and Carlos 13.1 Introduction Pyridofuropyrimidine Derivatives: From a Chemical Tool to a Development Candidate 208 the First Dual Inhibitor to Enter Clinical Trials Outlook 216 Acknowledgements 217 References 217 Chapter 14 Discovery of Multi-Target Inhibitors 221 Xiong Cai and Changgeng Qian 14.1 Introduction a Potent Multi-Target EGFR, HER2, and HDAC Inhibitor Compound Design and Synthesis In Vitro Potency and Mechanism of Action 224

8 Contents In Vivo Efficacy and Pharmacodynamics Pharmacokinetics and Safety Profile Clinical Progress and Results Overview of Multi-Target HDAC Inhibitors Conclusions 239 Acknowledgement 239 References 239 Chapter 15 Targeting Protein-Protein Interactions: Inhibitors of Bcl-2 and Bcl-xL 243 Michael D. Wendt 15.1 Introduction Rationale Discovery Program Screening and Hit to Lead Compounds Dual Inhibitors of Bcl-xL and Bcl Orally Bioavailable Compounds and ABT Conclusion 258 Acknowledgements 259 References 259 Chapter 16 Discovery of the Anti-Psychotic Drug, Ziprasidone 263 John A. Lowe, III 16.1 Introduction: Multi-Target Drug Design by Serendipity 263 Initial Efforts Towards an Atypical Antipsychotic Drug A New Direction and the Discovery of Ziprasidone 266 References 268 Chapter 17 The Rational Design of Triple Reuptake Inhibitors for the Treatment of Depression 270 Robert J. Weikert 17.1 Introduction Role of Dopamine in Depression Challenges Associated with Increased Dopamine Function Compound Target Profiles Genesis the Series 275

9 Contents Scaffold Hopping Aminopiperidine Series Aminopiperazine Series Pyrrolidine Series Ketone Series Conclusion 286 Acknowledgements 287 References 287 Chapter 18 Discovery of Multi-Target Agents for Neurological Diseases via Ligand Design 290 Maria Laura Bolognesi, Carlo Melchiorre, Cornells J. Van der Schyf and Moussa 18.1 The Rationale for Multi-Target Ligands in Alzheimer's and Parkinson's Diseases 290 Discovery of Memoquin, a Multi-Target Lead Candidate for AD The Scaffold: A Universal Template for Designing Multi-Target Ligands Memoquin's In Vitro and In Vivo Profile Alkylxanthines as Dual-Target-Directed Drug Candidates for PD Coffee, Caffeine, Adenosine Receptors, and Monoamine Oxidase: The PD Connection and Alkylxanthines 300 Discovery of Ladostigil, a Multi-Target Drug Candidate for AD and PD Ladostigil, an MTDL by Design 303 Basic Characteristics and Neuropharmacology of Ladostigil Conclusions 308 Acknowledgements 309 References 309 Chapter 19 Designing Drugs with Dual Activity: Novel Dual Angiotensin II and Endothelin Receptor Antagonists 316 Murugesan 19.1 Introduction 19.2 Angiotensin II Receptor Antagonists 317

10 Contents xxvii 19.3 System Endothelin Receptors Endothelin Receptor Antagonists Dual Angiotensin II and Endothelin Receptor Antagonists Scientific Rationale Rationale of DARA Drug Design In Vivo Activity DARA Clinical Studies of DARA Summary 331 Acknowledgements References 331 Chapter 20 Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE) 335 Stephen P. East, Lloyd G. Czaplewski and David J. Haydon 20.1 Introduction Function of Bacterial Type II Topoisomerases Structural Features of Protein Complexes of GyrB and ParE Ethyl Urea Inhibitors of GyrB and ParE Triazolopyridines Imidazopyridines Benzothiazoles/Thiazolopyridines Imidazopyridazines Pyridines Summary and Outlook 349 References 351 Epilogue 353 Subject Index 356