Lead Generation -  - ebook

Lead Generation ebook

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In this comprehensive two-volume resource on the topic senior Lead Generation medicinal chemists present a coherent view of the current methods and strategies in industrial and academic Lead Generation. This is the first book to combine both standard and innovative approaches in comparable breadth and depth, including several recent successful Lead Generation case studies published here for the first time. Beginning with a general discussion of the underlying principles and strategies, individual Lead Generation approaches are described in detail, highlighting their strengths and weaknesses, along with all relevant bordering disciplines like e.g. target identification and validation, predictive methods, molecular recognition or lead quality matrices. Novel Lead Generation approaches for challenging targets like DNA-encoded library screening or chemical biology approaches are treated here side by side with established methods as high throughput and affinity screening, knowledge- or fragment-based Lead Generation, and collaborative approaches. Within the entire book, a very strong focus is given to highlight the application of the presented methods, so that the reader will be able to learn from real life examples. The final part of the book presents several Lead Generation case studies taken from different therapeutic fields, including diabetes, cardiovascular and respiratory diseases, neuroscience, infection and tropical diseases. The result is a prime knowledge resource for medicinal chemists and for every scientist involved in Lead Generation.

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Liczba stron: 1431




Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

Dedication

List of Contributors

Preface

References

A Personal Foreword

Part I: Introduction to Lead Generation

1: Introduction: Learnings from the Past – Characteristics of Successful Leads

Acknowledgments

References

2: Modern Lead Generation Strategies

2.1 Lead Generation Greatly Influences Clinical Candidate Quality

2.2 Screening of Compound Libraries has Undergone a Major Paradigm Change

2.3 New Chemical Modalities are Available to Tackle Difficult Targets

2.4 As Demands have Increased, New Lead Generation Methods Emerged

2.5 How do Lead Generation Chemists Meet These Challenges and Subsequently Provide Their Lead Optimization Colleagues with High-Quality Lead Series?

References

Part II: The Importance of Target Identification for Generating Successful Leads

3: “Ligandability” of Drug Targets: Assessment of Chemical Tractability via Experimental and In Silico Approaches

3.1 Introduction

3.2 The Concept of Ligandability

3.3 The Intersection of Ligandability and Human Disease Target Space

3.4 Practical Examples of the Use of Fragment Screening for Ligandability Assessment

3.5 Conclusions and Outlook

References

4: Chemistry-Driven Target Identification

4.1 Introduction

4.2 Chemistry-Driven Target Discovery: Enabling Biology

4.3 Chemistry for Target Discovery

4.4 Small-Molecule Target Identification Techniques

4.5 Conclusions

References

Part III: Hit Generation Methods

5: Lead Generation Based on Compound Collection Screening

5.1 Introduction

5.2 Screening of Existing Collections: the General Workflow

5.3 Generation of New Screening Compounds

5.4 Other Concepts

5.5 Summary and Outlook

References

6: Fragment-Based Lead Generation

6.1 Introduction

6.2 Screening Methods

6.3 Hit Validation

6.4 Ligand Efficiency and Other Metrics

6.5 Hit Optimization

6.6 Fragment Growing

6.7 Fragment Linking

6.8 Protein–Protein Interactions

6.9 GPCRs

6.10 Computational Approaches

6.11 Conclusions

References

7: Rational Hit Generation

7.1 Introduction

7.2 Lead Generation: Transition State and Substrate Analogs

7.3 Hit Generation by Rational Library Design

7.4 Hit Generation by Virtual Screening

7.5 Hit Generation by Scaffold Replacement Technologies

7.6 Hit Generation by Chemogenomics Approaches

7.7 Summary

References

8: Competitive Intelligence–based Lead Generation and Fast Follower Approaches

8.1 Introduction

8.2 Competitive Intelligence-based Approach

8.3 Fast Follower Approach

References

9: Selective Optimization of Side Activities: An Alternative and Promising Strategy for Lead Generation

9.1 Introduction

9.2 Definition, Rational, and Concept of the SOSA Approach

9.3 Drugs in Other Drugs: Drug as Fragments

9.4 Drug Repositioning and Drug Repurposing

9.5 The SOSA Approach and Analog Design

9.6 Patentability and Interference Risk of the SOSA Approach

9.7 Case Studies and Examples

9.8 Conclusions

References

10: Lead Generation for Challenging Targets

10.1 Introduction

10.2 DNA-Encoded Library Technology in Lead Generation

10.3 Stapled Peptide

10.4 Phenotypic Screening

10.5 Summary

References

11: Collaborative Approaches to Lead Generation

11.1 Introduction

11.2 Creativity

11.3 Speed

11.4 Risk Sharing

11.5 Intellectual Property

11.6 Costs

11.7 Management

11.8 Lilly's Open Innovation Drug Discovery

11.9 Molecular Library Program

11.10 EU Openscreen

11.11 European Lead Factory

11.12 Medicines for Malaria Venture

11.13 Open Source Malaria Project

11.14 Drugs for Neglected Diseases Initiative

11.15 Open Lab Foundation

11.16 Scientists Against Malaria

11.17 Open Source Drug Discovery

11.18 TB Alliance

11.19 Summary

References

Part IV: Converting Hits to Successful Leads

12: A Medicinal Chemistry Perspective on the Hit-to-Lead Phase in the Current Era of Drug Discovery

12.1 Introduction

12.2 Active to Hit Processes

12.3 Target Potency: Energetics of Binding

12.4 Addressing Vast Chemical Space: HtL Strategies

12.5 Matched Pair Analysis

12.6 The Role of Hydrophobicity and HtL

12.7 Probing H-Bond Donors and Acceptors

12.8 Structure Based DD in HtL

12.9 Statistical Molecular Design

12.10 Hit to Lead is not Lead Optimization

12.11 Summary

References

13: Molecular Recognition and Its Importance for Fragment-Based Lead Generation and Hit-to-Lead

13.1 Introduction

13.2 Brief Summary of the Main Factors that Govern Molecular Interactions

13.3 Thermodynamics of Molecular Interactions and Impact on Hit Finding and Optimization

13.4 Enthalpy as a Key Decision Tool in Medicinal Chemistry

13.5 Importance of Enthalpic Interactions: Drivers of Selectivity and Specificity?

13.6 Fragment Screening Hit Optimization: Fragment Linking

13.7 Interstitial Waters and Their Usefulness: Case Studies on HSP-90

13.8 Fragments to Find Hot Spots in Binding Pockets

13.9 Nonclassical Hydrogen Bonds – Interactions of Halogen Atoms with Π-Systems and Carbonyl Groups: Factor Xa and Cathepsin L

13.10 Binding Mode Dependency of the Experimental Conditions and Chemical Framework of Ligand

13.11 Cooperativity in Binding: DAO or DAAO D-Amino Acid Oxidase

References

14: Affinity-Based Screening Methodologies and Their Application in the Hit-to-Lead Phase

14.1 Introduction

14.2 Nuclear Magnetic Resonance Spectroscopy

14.3 Optical Biosensors: Surface Plasmon Resonance and Optical Waveguide Grating

14.4 Isothermal Titration Calorimetry

14.5 Thermal Shift Assay

14.6 Mass Spectrometry Approaches

14.7 Encoded Library Technologies

14.8 Emerging Technologies: Microscale Thermophoresis and Backscattering Interferometry

References

15: Predictive Methods in Lead Generation

15.1 Introduction

15.2 Compound Property Prediction

15.3 Multiparameter Optimization: Identifying High-Quality Compounds

15.4 De Novo Design: Guiding the Exploration of Novel Chemistry

15.5 Selection: Balancing Quality with Diversity

15.6 Conclusions

References

16: Lead Quality

16.1 Introduction

16.2 Properties in Drug Design

16.3 Optimizing Properties: Useful Rules, Guides, and Simple Metrics for Early-Stage Projects

16.4 Predicted Dose to Man as a Measure of Early- and Late-Stage Lead Quality

16.5 Summary

References

Part V: Hypothesis-driven Lead Optimization

17: The Strategies and Politics of Successful Design, Make, Test, and Analyze (DMTA) Cycles in Lead Generation

17.1 DMTA Cycles: Perspectives from History

17.2 Test: What Assays, in What Order, and Why?

17.3 Additional Advice for “Test” Component of DMTA

17.4 Design: What to Make and Why?

17.5 Additional Advice for “Design” Component of DMTA

17.6 Make: Challenges and Strategies for Synthesis

17.7 Additional Advice for the “Make” Component of DMTA

17.8 Analyze: Making Sense of What's Been Done and Formulating Sensible Plans for the Next Designs

17.9 Additional Advice for “Analyze” Component of DMTA

17.10 Results: Do Lead Optimization Teams Get What They Need?

References

Part VI: Recent Lead Generation Success Stories

18: Lead Generation Paved the Way for the Discovery of a Novel H3 Inverse Agonist Clinical Candidate

18.1 Introduction

18.2 Hit Identification

18.3 Lead Generation

18.4 Lead Optimization and Candidate Selection

18.5 Conclusions

Acknowledgments

References

19: Vorapaxar: From Lead Identification to FDA Approval

19.1 Introduction

19.2 Background Information on Antiplatelet Agents

19.3 Thrombin Receptor (Protease-activated Receptor-1) Antagonists as a Novel Class of Antiplatelet Agents

19.4 Mechanism of Thrombin Receptor Activation

19.5 Preclinical Data Supporting the Antiplatelet Effect of Thrombin Receptor Antagonists

19.6 Himbacine-derived Thrombin Receptor Antagonists

19.7 Conclusions

Abbreviations

Acknowledgments

References

20: Lead Generation Approaches Delivering Inhaled β2-Adrenoreceptor Agonist Drug Candidates

20.1 Introduction

20.2 Lead Generation Exercises to Discover β2AR Agonist Clinical Candidates

20.3 AstraZeneca Lead Generation Exercises to Discover β2AR Agonist Clinical Candidates

20.4 Summary

References

21: GPR81 HTS Case Study

21.1 General Remarks

21.2 The Target

21.3 Screening Cascade

21.4 Compound Selection (10 k Validation Set)

21.5 HTS

21.6 Hit Evaluation

21.7 Alternative Lead Generation Strategies

21.8 Conclusions

References

22: Development of Influenza Virus Sialidase Inhibitors

22.1 Introduction

22.2 Targets for Anti-influenza Drug Development: Receptor Binding and Receptor Cleavage

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