Mass Spectrometry for Drug Discovery and Drug Development

Facilitates the discovery and development of new, effectivetherapeutics

With coverage of the latest mass spectrometry technology, thisbook explains how mass spectrometry can be used to enhance almostall phases of drug discovery and drug development, including newand emerging applications. The book′s fifteen chapters have beenwritten by leading pharmaceutical and analytical scientists. Theircontributions are based on a thorough review of the currentliterature as well as their own experience developing new massspectrometry techniques to improve the ability to discover anddevelop new and effective therapeutics.

Mass Spectrometry for Drug Discovery and Drug Developmentbegins with an overview of the types of mass spectrometers thatfacilitate drug discovery and development. Next it covers:

HPLC high–resolution mass spectrometry for quantitativeassays Mass spectrometry for siRNA Quantitative analysis of peptides Mass spectrometry analysis of biological drugs Applications that support medicinal chemistryinvestigations Mass spectrometry imaging and profiling

Throughout the book, detailed examples underscore the growingrole of mass spectrometry throughout the drug discovery anddevelopment process. In addition, images of mass spectra areprovided to explain how results are interpreted. Extensivereferences at the end of each chapter guide readers to the primaryliterature in the field.

Mass Spectrometry for Drug Discovery and Drug Developmentis recommended for readers in pharmaceutics, including medicinalchemists, analytical chemists, and drug metabolism scientists. Allreaders will discover how mass spectrometry can streamline andadvance new drug discovery and development efforts.

Contributors ix

Preface xi

1 Overview of the Various Types of Mass Spectrometers that areUsed in Drug Discovery and Drug Development 1
Gérard Hopfgartner

2 Utility of High–Resolution Mass Spectrometry for New DrugDiscovery Applications 37
William Bart Emary and Nanyan Rena Zhang

3 Quantitative Mass Spectrometry Considerations in a RegulatedEnvironment 55
Mohammed Jemal and Yuan–Qing Xia

4 Mass Spectrometry for Quantitative In Vitro ADME Assays97
Jun Zhang and Wilson Z. Shou

5 Metabolite Identifi cation Using Mass Spectrometry in DrugDevelopment 115
Natalia Penner, Joanna Zgoda–Pols, and Chandra Prakash

6 MS Analysis of Biological Drugs, Proteins, and Peptides149
Yi Du, John Mehl, and Pavlo Pristatsky

7 Characterization of Impurities and Degradation Products inSmall Molecule Pharmaceuticals and Biologics 191
Hui Wei, Guodong Chen, and Adrienne A. Tymiak

8 Liquid Extraction Surface Analysis (LESA): A New MassSpectrometry–Based Technique for Ambient Surface Profiling221
Daniel Eikel and Jack D. Henion

9 MS Applications in Support of Medicinal Chemistry Sciences239
Maarten Honing, Benno Ingelse, and Birendra N. Pramanik

10 Imaging Mass Spectrometry of Proteins and Peptides 277
Michelle L. Reyzer and Richard M. Caprioli

11 Imaging Mass Spectrometry for Drugs and Metabolites 303
Stacey R. Oppenheimer

12 Screening Reactive Metabolites: Role of LiquidChromatography High–Resolution Mass Spectrometry inCombination with Intelligent Data Mining Tools339
Shuguang Ma and Swapan K. Chowdhury

13 Mass Spectrometry of siRNA 357
Mark T. Cancilla and W. Michael Flanagan

14 Mass Spectrometry for Metabolomics 387
Petia Shipkova and Michael D. Reily

15 Quantitative Analysis of Peptides with Mass Spectrometry:Selected Reaction Monitoring or High–Resolution Full Scan?403
Lieve Dillen and Filip Cuyckens

Index 427

WALTER A. KORFMACHER, PhD, is Director of Bioanalysis atGenzyme, a Sanofi company, and Associate Editor at the Journalof Mass Spectrometry. Previously, he held positions at theFDA′s National Center for Toxicological Research, Schering–PloughResearch Institute, Merck Research Laboratories, and MedpaceBioanalytical Laboratories. Dr. Korfmacher is an internationalleader in developing mass spectrometry techniques and strategiesfor new drug discovery and drug metabolism applications. A 2009recipient of the CPSA Distinguished Analytical Scientist Award, hehas published more than 150 articles in the scientific literatureand made more than eighty presentations at various scientificforums.