Breakthroughs in combinatorial chemistry and molecular biology, as well as an overall industry trend toward accelerated development, mean the rate of sample generation now far exceeds the rate of sample analysis in the pursuit of producing new and better pharmaceuticals. LC/MS is an analytical tool that helps the researcher identify the most promising sample early in the selection process, effectively creating a shortcut to finding new drugs. This book is the first to describe LC/MS applications within the context of drug development, including the discovery, preclinical, clinical, and manufacturing phases. In addition to the thorough technical analysis of this tool, LC/MS Applications in Drug Development provides perspective on the significant changes in strategies for pharmaceutical analysis. A process overview of drug development from an analytical point of view is provided along with essential data required to successfully bring a drug to market. The incorporation of LC/MS is illustrated from target to product. Chapters pertaining to the discovery process itself include: Proteomics Glycoprotein Mapping Natural Products Dereplication Lead Identification Screening Open-Access LC/MS In Vitro Drug Screening Written for both the analytical chemist who uses LC/MS applications and the pharmaceutical scientist who works with the drugs they produce, LC/MS Applications in Drug Development is the premier reference on the subject.

Table of Contents:
Preface ix Acknowledgments xi 1. Introduction 1 Emerging Analytical Needs 1 Integration of LC/MS into Drug Development 3 Partnerships and Acceptance 6 Overview 10 2. Drug Development Overview 11 Analysis Perspectives 11 The Four Stages of Drug Development 12 Drug Discovery 14 Preclinical Development 15 Clinical Development 16 Manufacturing 17 3. Accelerated Drug Development 19 Accelerated Development Strategies 20 Quantitative and Qualitative Process Elements 20 Quantitative Process Pipeline 24 Qualitative Process Pipeline 25 Motivating Factors 27 Analysis Opportunities for Accelerated Development 28 Full-Time Equivalent 28 Sample Throughput Model 29 Elimination Model 29 Rate-Determining Event Model 31 Accelerated Development Perspectives 33 4. LC/MS Development 34 The Elements of LC/MS Application 34 HPLC 35 Mass Spectrometry 35 LC/MS Interface 36 LC/MS Growth 38 5. Strategies 41 Standard Methods 43 Template Structure Identification 46 Databases 49 Screening 50 Integration 53 Miniaturization 55 Parallel Processing 56 Visualization 58 Automation 61 Summary 63 6. LC/MS Applications 65 Drug Discovery 65 Proteomics 68 Protein Expression Profiling 70 Quantitation 76 Glycoprotein Mapping 78 Natural Products Dereplication 83 Lead Identification Screening 88 Bioaffinity Screening 89 Combinatorial Library Screening 92 Open-Access LC/MS 96 Structure Confirmation 97 High Throughput 100 Purification 102 Combinatorial Mixture Screening 103 In Vivo Drug Screening 106 Pharmacokinetics 109 In Vitro Drug Screening 115 Metabolic Stability Screening 118 Membrane Permeability 119 Drug-Drug Interaction 121 Metabolite Identification 122 Preclinical Development 123 Metabolite Identification 125 Impurity Identification 132 Degradant Identification 140 Clinical Development 145 Quantitative Bioanalysis—Selected Ion Monitoring 148 Quantitative Bioanalysis—Selected Reaction Monitoring 152 Quantitative Bioanalysis—Automated Solid-Phase Extraction 156 Quantitative Bioanalysis—Automated On-Line Extraction 162 Metabolite Identification 165 Degradant Identification 168 Manufacturing 171 Impurity Identification Using Data-Dependent Analysis 173 Peptide Mapping in Quality Control 176 Patent Protection 178 7. Future Applications and Prospects 183 Workstations 183 Multidimensional Analysis 186 Miniaturization 187 Information Management 189 Strategic Outsourcing 190 Summary 191 8. Perspectives on the Future Growth of LC/MS 192 9. Conclusions 195 Glossary 197 References 205 Index 235