The Practice of Medicinal Chemistry, 4th Edition

Book Review

The Practice of Medicinal Chemistry, 4th Edition.

DDR

DRUG DEVELOPMENT RESEARCH 77 : 103–104 (2016)

Camille Wermuth, David Aldous, Pierre Raboisson and Didier Rognan. Academic Press, London, 2015. ISBN Print 9780124172050 $150; eBook 9780124172135. $150. pp xxii 1 880.

The 4th edition of Wermuth’s The Practice of Medicinal Chemistry, marks the 20th year that this indispensable monograph - often referred to as the “bible” of medicinal chemistry – has been part of the armamentarium of the practicing medicinal chemist. As with previous editions, the present edition provides a diverse, multi-authored yet comprehensive update on the current state of the art in the science of medicinal chemistry. Of especial note is the welcome and overdue expansion of potential drug targets beyond the well worn topic of GPCRs. The book is a pleasure visually – hard not to casually delve into and find a topic of immediate interest - and printed on heavier stock than the 3rd Edition making it more easily readable than the bleed through of the text on the previous Edition. It makes extensive use of color to walk the reader through the logic of the modifications of various pharmacophore templates to improve their “drugability”. The book is also appears more accessible to biologists than the previous edition and is thus a mandatory text for all non-chemists involved in the drug discovery process helping to provide useful insights into the numerous lead optimization strategies that are discussed throughout the book. Two noteworthy sets of “rules” contained in this book are the seven strategic application rules for compound modification outlined by Wermuth et al., in Chapter 12 (pp. 312-317) that were also included in the 3rd Edition that are now joined by the equally pragmatic, more conceptual six rules of Sir James Black (Black’s Rules) usefully outlined by Hopkins in Chapter 16 (p. 396). These 13 rules would be perfect as a laminated “cheat sheet” that the publisher could use in publicizing the book and also as an extremely useful tool to guide drug discovery project team meetings. Together they would enable a common understanding at the initiation of a project with their use to benchmark progress improving the outcomes of a lead optimization campaign and in facilitating a successful translational process. The Practice of Medicinal Chemistry has been significantly restructured from the 3rd Edition published in 2008 and is now divided into 6 sections: I. General C 2016 Wiley Periodicals, Inc. V

Aspects of Medicinal Chemistry; II. Lead Compound Discovery Strategies; III: Primary Exploration of Structure-Activity Relationships; IV, Substituents and Functions; V, Spatial Organization, Receptor Mapping and Molecular Modeling and; VI, Chemical Modifications Influencing the Pharmacokinetic Properties. The monograph includes 36 chapters covering 862 pages of text together with the usual prefaces and index. These include - Chapter 1. Medicinal Chemistry, Definitions and Objectives, Drug Activity Phases. Drug Classification Schemes (Imming); Chapter 2. Evaluation of the Biological Activity of Compounds: Techniques and Mechanism of Action Studies (Dougall and Unitt); Chapter 3. Drug Targets, Target Identification, Validation, and Screening (Van Den Broeck); Chapter 4. Strategies in the Search for New Lead Compounds or Original Working Hypotheses (Wermuth et al.,); Chapter 5. Natural Products as Pharmaceuticals and Sources for Lead Structures (Newman et al.,); Chapter 6. In Silico Screening: Hit Finding from Database Mining (Rodrigues and Schneider); Chapter 7. Fragment Based Drug Discovery (Velvadapu et al.,); Chapter 8. Molecular Variations Based on Isosteric Replacements (Ciapetti and Giethelin); Chapter 9. Ring Transformations (Morice and Wermuth); Chapter 10. Macrocycles: Under-Explored and Poorly Exploited Drug Class Despite the Proven Therapeutic Potential (Raboisson); Chapter 11. Conformational Restriction and Steric Hindrance in Medicinal Chemistry (Wipf et al.,); Chapter 12. Application Strategies for the Primary Structure–Activity Relationship Exploration (Wermuth et al.,); Chapter 13. Substituent Groups (Baszzini and Wemuth); Chapter 14. The Role of Functional Groups in Drug–Receptor Interactions (Schaeffer); Chapter 15. Compound Properties and their Influence on Drug Quality (Chen et al.,); Chapter 16. Pharmacological Space (Hopkins); Chapter 17. Systems Biology: A New Paradigm for Drug Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/ddr.21293

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Discovery (Hussein et al.,); Chapter 18. Optical Isomerism in Drugs (Wermuth); Chapter 19. Multitarget Drugs: Strategies and Challenges for Medicinal Chemists (Morphy and Rankovic); Chapter 20. Selective Optimization of Side Activities (SOSA) in Drug Discovery (Jonckers); Chapter 21. Pharmacophore Identification and PseudoReceptor Modeling (Wolber and Sippl); Chapter 22. Protein Crystallography and Drug Discovery (Rondeau and Schreuder); Chapter 23. Physiological Aspects Determining the Pharmacokinetic Properties of Drugs (Boussery et al.,); Chapter 24. Biotransformation Reactions and their Enzymes (Testa and Clement); Chapter 25. Biotransformations Leading to Toxic Metabolites: Chemical Aspects (Macherey and Dansette); Chapter 26. Drug Transport Mechanisms and their Impact on the Disposition and Effects of Drugs (Scherrmann); Chapter 27. Strategies for Enhancing Oral Bioavailability and Brain Penetration (Gross); Chapter 28. Designing Prodrugs and Bioprecursors (Choi-Sledeski and Wermuth); Chapter 29. Drug Delivery with Organic Solvents or Colloidal Dispersed Systems (Riebesehl); Chapter 30. Preparation of Water-Soluble Compounds by Covalent Attachment of Solubilizing Moieties (Wermuth and Lesuisse); Chapter 31. Improving the Water-Solubility of Compounds by Molecular Modification to Disrupt Crystal Packing (Ishikwa and Hashimoto); Chapter 32. Chemical and Physicochemical Approaches to Solve Formulation Problems (Leiberman and Vemuri); Chapter 33. Discover a Drug Substance, Formulate, and Develop It to a Product (deMontigny et al.,); Chapter 34. Drug Nomenclature (Balocco Mattavelli et al.,); Chapter 35. Web Alert: Using the Internet for Medicinal Chemistry (Cavalla); Chapter 36. Protection of Inventions in Medicinal Chemistry (Luthi and Brice). As a result of the author roster and the editors, the book is heavily focused on the various strategies used in the European drug discovery arena to optimize leads that tend to involve a more thoughtful and intellectuallydriven lead optimization approach than the brute strength combinatorial chemistry approach that was so pervasive in the US in the 1990s and proved so disastrous to advancing success in drug discovery. It also provides a somewhat different (and physically less weighty) perspective to what can be considered as its main competitors, the 6,000 page plus, nearly $3000 8 volume set of Burger’s Medicinal Chemistry, Drug Discovery and Development, 7th Edition last published in 2010 and the 7,200 page, 8 volume $8,000 Comprehensive Medicinal Chemistry II (2007) both of which are out of date although the latter text is currently in revision for a 2017 publication. Given the variety of topics covered and the multiplicity of authors there are inevitable disconnects, a major one being a recapitulation of the infatuation with “systems biology” (Chapter 17), once again described as a “new” Drug Dev. Res.

paradigm when it differs marginally - if at all - from the pharmacological approach that has driven drug discovery to date. Other omissions/oversights/disconnects include: a lack of necessary emphasis of the inherent diversity/complexity of target families (especially transporters) and signaling pathways – both of which could be the topic of additional chapters; an absence of detail on the challenges involved in blood brain barrier drug delivery; a lack of consideration in the “fast follower” strategy (Chapter 3, pp. 50–51) of new chemical entities other than analogs of the first in class drug; increased any coverage of nanotechnology; and the surprising absence of Copeland’s key concept of compound residence time which has very major implications for the better understanding of drug efficacy. While Copeland’s excellent book, Evaluation of Enzyme Inhibitors in Drug Discovery: A Guide for Medicinal Chemists and Pharmacologists. 2nd Edition is mentioned in passing on page 22, the topic of residence time could not be found in the index and or in this reader’s search of the printed text or an Adobe “find” search of the pdf of the e-book. This may well be due to the fact - as noted by Copeland (2016) that “a surprising number of scientists remain unaware of this model”. Minor irritations include the use of abbreviations that are neither adequately explained nor placed in appropriate context, e.g., ACT and TACT on p.12 and LE, BEI, SILE, LLE and LELP on p.163. While the topic of assay interference compounds is nicely covered on p. 35, the widely used abbreviation, PAINS (pan-assay interference compounds; Nature 2014 513, 481) is absent. These are however, very minor points in a monograph that represents a quantal leap from the previous edition. This reflects both the numerous advances in target deconvolution/validation, medicinal chemistry and compound evaluation technologies that have occurred since 2008 and the considerable and concerted efforts of the Editors and Authors to produce a cohesive and useful monograph in an era where printed books are becoming an anomaly and where individual papers and reviews – good as they may be - do not provide the consistency and context of a dedicated text in understanding the big picture of an area of research. This monograph is highly recommended for graduate students in the medicinal chemistry and drug discovery sciences. Michael Williams Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, IL REFERENCE Copeland RA. 2016. The drug-target residence time model: a 10year retrospective. Nature Rev Drug Discov 15, doi:10.1038/ nrd.2015.18.