NMR in Pharmaceutical Science E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Serie: EMR Books
• Sprache: Englisch

Seitenzahl: 1233

Veröffentlichungsjahr: 2015

Beschreibung

NMR in Pharmaceutical Sciences is intended to be a comprehensive source of information for the many individuals that utilize MR in studies of relevance to the pharmaceutical sector. The book is intended to educate and inform those who develop and apply MR approaches within the wider pharmaceutical environment, emphasizing the toolbox that is available to spectroscopists and radiologists.

This book is structured on the key processes in drug discovery, development and manufacture, but underpinned by an understanding of fundamental NMR principles and the unique contribution that NMR (including MRI) can provide. After an introductory chapter, which constitutes an overview, the content is organised into five sections. The first section is on the basics of NMR theory and relevant experimental methods. The rest follow a sequence based on the chronology of drug discovery and development, firstly 'Idea to Lead' then 'Lead to Drug Candidate', followed by 'Clinical Development', and finally 'Drug Manufacture'.  The thirty one chapters cover a vast range of topics from analytical chemistry, including aspects involved in regulatory matters and in the prevention of fraud, to clinical imaging studies.

Whilst this comprehensive volume will be essential reading for many scientists based in pharmaceutical and related industries, it should also be of considerable value to a much wider range of academic scientists whose research is related to the various aspects of pharmaceutical R&D; for them it will supply vital understanding of pharmaceutical industrial concerns and the basis of key decision making processes.

About eMagRes Handbooks

eMagRes (formerly the Encyclopedia of Magnetic Resonance) publishes a wide range of online articles on all aspects of magnetic resonance in physics, chemistry, biology and medicine. The existence of this large number of articles, written by experts in various fields, is enabling the publication of a series of eMagRes Handbooks on specific areas of NMR and MRI. The chapters of each of these handbooks will comprise a carefully chosen selection of eMagRes articles. In consultation with the eMagRes Editorial Board, the eMagRes handbooks are coherently planned in advance by specially-selected Editors, and new articles are written to give appropriate complete coverage. The handbooks are intended to be of value and interest to research students, postdoctoral fellows and other researchers learning about the scientific area in question and undertaking relevant experiments, whether in academia or industry.

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Leseprobe

Table of Contents

Cover

Series Page

Title Page

Copyright

eMagRes

International Advisory Board

Contributors

Series Preface

Preface

Abbreviations and Acronyms

Part A: Introduction

Chapter 1: Drug Discovery and Development: The Role of NMR

1.1 Introduction to Drug Discovery and Development and the Role of NMR

1.2 NMR Spectroscopy in Drug Discovery and Development

1.3 New Applications of NMR Spectroscopy in Pharmaceutical R&D

1.4

In vivo

MRS and MRI

1.5 Future Developments

References

Part B: NMR Theory & Experimental Methods

Chapter 2: Modern NMR Pulse Sequences in Pharmaceutical R&D

2.1 Introduction

2.2 Initial Sample Adjustments

2.3 One-dimensional Methods

2.4 Pulse Sequences for 2D NMR Spectroscopy

2.5 Conclusions

Related Articles in eMagRes

References

Further Reading

Chapter 3: NMR Theory & Experimental MethodsExperimental NMR Methods for Pharmaceutical Research and Development

3.1 Introduction

3.2 NMR Hardware, Analytical Conditions

3.3 NMR-related Workflows

3.4 Quality Control

3.5 Conclusions

Related Articles in eMagRes

References

Chapter 4: 19F NMR Spectroscopy: Applications in Pharmaceutical Studies

4.1 Introduction

4.2 Practical Aspects of

19

F NMR Spectroscopy

4.3 Small Molecule Studies of Pharmaceutical Interest

4.4 Application to Fluorine-Labeled Macromolecules

4.5 Drug Screening Activities

4.6 Applications in Drug Metabolism Studies

4.7

19

F NMR Spectroscopy In Vivo

Related Articles in eMagRes

References

Chapter 5: Quantitative NMR Spectroscopy in Pharmaceutical R&D

5.1 Introduction

5.2 Basic Principles of

q

NMR

5.3 Signal Separation/Overlap

5.4 Quantification Methods

5.5 Applications

5.6 Conclusion

Acknowledgments

References

Chapter 6: High-throughput NMR in Pharmaceutical R&D

6.1 Introduction

6.2 Overall Process View

6.3 Workflow – Purity and Identity of Solid Samples

6.4 Workflow – Purity and Identity of Screening Solutions

6.5 Workflow – Fragment-based Drug Discovery

6.6 Common Themes

6.7 Getting Faster

6.8 Summary

References

Chapter 7: Multivariate Data Analysis Methods for NMR-based Metabolic Phenotyping in Pharmaceutical and Clinical Research

7.1 Introduction

7.2 Raw Analytical Signal Processing

7.3 Exploratory Analysis of H NMR-based Metabolic Phenotypes

7.4 Predictive Analysis of H NMR-based Metabolic Phenotypes

7.5 Time-course Analysis of NMR-based Metabolic Phenotypes

7.6 Conclusions

Related Articles in eMagRes

References

Part C: Idea to Lead

Chapter 8: The Role of NMR in Target Identification and Validation for Pharmaceutical R&D

8.1 Introduction: What is Drug Discovery?

8.2 Drug Targets

8.3 Target Identification and Validation

8.4 Application of NMR in Target Identification and Validation

Acknowledgments

References

Chapter 9: High-resolution MAS NMR of Tissues and Cells

9.1 Introduction

9.2 The Developments

9.3 Applications

9.4 Conclusions

Related Articles in eMagRes

References

Chapter 10: NMR Studies of Inborn Errors of Metabolism

10.1 Introduction

10.2 Body Fluid NMR

10.3 Applications of NMR in IEM Diagnosis

Related Articles in eMagRes

References

Chapter 11: NMR-based Structure Confirmation of Hits and Leads in Pharmaceutical R&D

11.1 Introduction

11.2 Why Is It Necessary?

11.3 When Should the Structure Confirmation Be Carried Out?

11.4 What Are the Benefits?

11.5 How Is Structure Confirmation Carried Out?

11.6 How Bad Can It Get?

11.7 Conclusion

Related Articles in eMagRes

References

Chapter 12: Fragment-based Drug Design Using NMR Methods

12.1 Introduction

12.2 Fragment-based Drug Design vs High-throughput Screening

12.3 FBDD Approaches

12.4 Fragment Library

12.5 Target Druggability

12.6 Target-based vs Ligand-based FBDD NMR Methods

12.7 Protein Target Production

12.8 NMR-based Screening Experiments

12.9

19

F NMR Screening

12.10 Hit Validation by NMR and Validation of NMR Fragment Hits

12.11 Nonspecific Binding

12.12 Fragment Prioritization

12.13 Hit-to-Lead

12.14 Linker Design

12.15 Protein–Ligand Affinities

12.16 Protein–Ligand Structure Determination

12.17 Clinical Candidates Originating from FBDD

Related Articles in eMagRes

References

Chapter 13: Hit Discovery from Natural Products in Pharmaceutical R&D

13.1 Introduction

13.2 Practical Aspects of NMR Spectroscopic Experiments on Natural Products

13.3 Advances in NMR Acquisition and Data Processing

13.4

1

H NMR Spectroscopic Screening of Natural Product Extracts

13.5 Micro NMR Spectroscopy and Cryogenic NMR Probes

13.6 NMR Spectroscopy of Natural Products Following Chromatography

13.7 Dereplication and Natural Product NMR Databases

13.8 Conclusions

Related Articles in eMagRes

References

Part D: Lead to Drug Candidate

Chapter 14: NMR-based Structure Determination of Drug Leads and Candidates

14.1 Introduction

14.2 Background to Structure Determination by NMR in the Pharmaceutical Industry

14.3 Information from NMR Experiments for Structure Determination

14.4 Constitution. Use of C NMR Chemical Shift Predictions and H–C Chemical Shift Correlations from HSQC and HMBC Spectra

14.5 Stereochemistry Problems. Proton–Proton Through-space Correlations

14.6 Use of the N Isotope

14.7 Examples Where H NMR Spectra are Broad or Contain More than One Species in Solution

14.8 Conclusions

References

Chapter 15: Mixture Analysis in Pharmaceutical R&D Using Hyphenated NMR Techniques

15.1 Introduction

15.2 Practical and Technical Considerations in LC–NMR

15.3 High-performance Liquid Chromatography–Nuclear Magnetic Resonance–Mass Spectrometry (HPLC–NMR–MS)

15.4 Applications of LC–NMR

15.5 Conclusions

Related Articles in eMagRes

References

Chapter 16: Conformation and Stereochemical Analysis of Drug Molecules

16.1 Introduction

16.2 Experimental Techniques

16.3 Analysis of NMR Results

16.4 Applications of Stereochemical and Conformational Studies in the Pharmaceutical Industry

16.5 Conclusions

Acknowledgments

Related Articles in eMagRes

References

Chapter 17: NMR Methods for the Assignment of Absolute Stereochemistry of Bioactive Compounds

17.1 Introduction

17.2 The Absolute Configuration and NMR Spectra

17.3 CDAs and Substrates

17.4 The Use of

13

C NMR for Assignment

17.5 The Assignment of Absolute Configuration of Monofunctional Compounds by Double Derivatization

17.6 Single Derivatization Methods for Alcohols and Amines

17.7 The Assignment of Polyfunctional Compounds

Related Articles in eMagRes

References

Chapter 18: Applications of Preclinical MRI/MRS in the Evaluation of Drug Efficacy and Safety

18.1 Introduction

18.2 Review of MRI/MRS Methods

18.3 Applications of MRI/MRS in Drug Discovery

18.4 Conclusions

18.5 Disclaimer

18.6 Conflict of Interests

Acknowledgment

Related Articles in eMagRes

References

Chapter 19: Practical Applications of NMR Spectroscopy in Preclinical Drug Metabolism Studies

19.1 Introduction

19.2 NMR in the Realm of ADME Discovery

19.3 Metabolite Concentrations versus Instrument Sensitivity

19.4 Sample Isolation

19.5 Quantitative NMR (qNMR) Spectroscopy

19.6 Discussion

References

Chapter 20: Preclinical Drug Efficacy and Safety Using NMR Spectroscopy

20.1 Introduction

20.2 Sample Types

20.3 Statistical Analysis of Metabonomic Data

20.4 Organ-specific Toxicities by NMR Spectroscopy-based Metabonomics

20.5 The COMET Consortium Project

20.6 Toxico/pharmacometabonomics

20.7 Conclusions

References

Chapter 21: Characterization of Pharmaceutical Compounds by Solid-state NMR

21.1 Introduction

21.2 Basic Experimental Methods

21.3 Emerging Experimental Methods

21.4 Crystalline Phases of Drug Substances and Excipients

21.5 Amorphous Phases of Drug Substances and Excipients

21.6 Drug Products

21.7 Conclusion

Acknowledgments

Related Articles in eMagRes

References

Chapter 22: Structure-based Drug Design Using NMR

22.1 Introduction

22.2 Protein Kinases

22.3 Protein Tyrosine Phosphatase 1B (PTP1B)

22.4 Ras Superfamily

22.5 Conclusions

Acknowledgments

References

Chapter 23: Pharmaceutical Technology Studied by MRI

23.1 Introduction

23.2 Practicalities

23.3 Applications

23.4 Future Developments

23.5 End Note

Acknowledgments

References

Further Reading

Part E: Clinical Development

Chapter 24: NMR-based Metabolic Phenotyping for Disease Diagnosis and Stratification

24.1 Introduction

24.2 NMR Spectroscopy and Metabolic Phenotyping

24.3 Conclusion

Acknowledgments

References

Chapter 25: NMR-based Pharmacometabonomics: A New Approach to Personalized Medicine

25.1 Introduction to Personalized Medicine

25.2 Introduction to Metabonomics and Pharmacometabonomics

25.3 The First Demonstrations of Pharmacometabonomics

25.4 The Current Status of Pharmacometabonomics