Part IV

Enabling strategies

Part V

Figure 3 A schematic representation of modern drug research and development (a), presented in parallel with the layout of this volume (b). (a) The major steps in drug R&D, showing target validation, discovery, and development, followed by the clinical phases and the postmarketing phase. Note the overlaps, which reflect the fact that many knowledge-expanding investigations are carried out after the next phases have begun, e.g., in vivo research in animals continues during the clinical phases, and clinical studies continue postmarketing for confirmatory and indication-enlarging purposes. Preclinical R&D has two objectives: activity and ADMET. These translate as efficacy and tolerance in the early clinical phases, to merge subsequently into the global objective of utility. (b) This part of the figure shows the content of this volume and how its parts correspond to the ADMET methodologies and technologies used in drug discovery and development. (The upper part is reproduced from Testa, B.; Kramer, S. D. Chem. Biodiv. (in press) with the kind permission of the copyright owner, Verlag Helvetica Chimica Acta in Zurich.)

As a result of this dual rationale, this volume has been organized to begin with the human patient; concretely with the clinical pharmacokinetic criteria good candidates are expected to fulfill. The first chapter (5.02 Clinical Pharmacokinetic Criteria for Drug Research), written by two renowned clinical pharmacologists, is thus the platform on which the volume is built. Part I (see Figure 3b) then examines in vivo animal models used in discovery and development (see 5.03 In Vivo Absorption, Distribution, Metabolism, and Excretion Studies in Discovery and Development). This is followed by a number of chapters presenting the biochemical bases of drug metabolism and toxification/detoxification.

Part 2 is dedicated to in vitro biological tools used to investigate the absorption, distribution, and metabolism of lead candidates, leads, and clinical candidates. As stressed above, relevance to in vivo and clinical behavior is a major concern. Part 3 covers the major physicochemical tools used in discovery and mainly in development to characterize ionization profile, solubility and dissolution, lipophilicity and permeation, and stability of leads and clinical candidates. Relevance to biological and clinical behavior is considered.

Part 4 is dedicated to in silico tools. The term 'in silico' was coined by the molecular biologist Antoine Danchin, whose quotation below offers a concise and cogent justification to our decision to dedicate the largest part of the volume to this methodology:

[I]nformatics is a real aid to discovery when analyzing biological functions____ [I] was convinced of the potential of the computational approach, which I called in silico, to underline its importance as a complement to in vivo and in vitro experimentation.50

Indeed, in silico tools have gained an irreplaceable significance in virtual experimentation by allowing medicinal chemists to predict physicochemical and ADMET properties of projected and existing molecules. But here again, relevance to 'wet' physicochemistry, biological properties, and clinical behavior is of paramount importance.

The volume ends with the short Part 5 where global tools (the biopharmaceutics classification system and metabonomics) and enabling strategies are presented.

With 45 chapters, this volume aims at informing by providing data and examples, and instructing by presenting a conceptual and logical framework. As such, careful students of this volume may find in it a didactic value even greater than that of the sum of its individual chapters. The hope is that this volume will retain its usefulness for many years to come, and we thank our contributors for their dedication and enthusiasm.


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Han Van de Waterbeemd studied physical organic chemistry at the Technical University of Eindhoven, the Netherlands, and then took a PhD in medicinal chemistry at the University of Leiden, the Netherlands. After carrying out postdoctoral research with Bernard Testa at the School of Pharmacy of the University of Lausanne, Switzerland, he took up a position at the same institution for 5 years. He also taught medicinal chemistry to pharmacy students at the universities of Berne and Basel in Switzerland from 1987 to 1997. In 1988 Han joined F Hoffmann-La Roche Ltd in Basel as head of the Molecular Properties Group. In 1997 he moved to Pfizer Central Research UK (now Pfizer Global Research and Development), and held various positions in the Department of Drug Metabolism, later called PDM (Pharmacokinetics, Dynamics, and Metabolism), including Head of Discovery and Head of Automation and In Silico ADME Technologies. In 2005 he moved to AstraZeneca to become global project leader of their Molecular Properties and In Silico ADMET Modeling system.

He has published more than 135 peer-reviewed papers and book chapters, and has (co)-edited 11 books. His research interests include physicochemical and structural molecular properties and their role in drug disposition, as well as the in silico modeling of ADMET properties. Han was secretary of The QSAR and Modeling Society between 1995 and 2005.

Bernard Testa studied pharmacy because he was unable to choose between medicine and chemistry. Because he was incapable of working in a community pharmacy, he undertook a PhD thesis on the physicochemistry of drug-macromolecule interactions. Because he felt himself to be not gifted enough for the pharmaceutical industry, he applied for a postdoctoral research position at Chelsea College, University of London, where he worked for 2 years under the supervision of Prof Arnold H Beckett. And because these were easy times, he was called upon to become assistant professor at the University of Lausanne, Switzerland, becoming full professor and Head of Medicinal Chemistry in 1978. Since then, he has tried to repay his debts by fulfilling a number of local and international commitments, e.g., Dean of the Faculty of Sciences (1984-86), Director of the Geneva-Lausanne School of Pharmacy (1994-96 and 1999-2001), and President of the University Senate (1998-2000). He has written four books and edited 29 others, and (co)-authored 450 research and review articles in the fields of drug design and drug metabolism. During the years 1994-98, he was the Editor-Europe of Pharmaceutical Research, the flagship journal of the American

Association of Pharmaceutical Scientists (AAPS), and he is now the co-editor of the new journal Chemistry and Biodiversity. He is also a member of the Editorial Board of several leading journals (e.g., Biochemical Pharmacology, Chirality, Drug Metabolism Reviews, Helvetica Chimica Acta, Journal of Pharmacy and Pharmacology, Medicinal Research Reviews, Pharmaceutical Research, and Xenobiotica). He holds Honorary Doctorates from the Universities of Milan, Montpellier, and Parma, and was the 2002 recipient of the Nauta Award on Pharmacochemistry given by the European Federation for Medicinal Chemistry. He was elected a Fellow of the AAPS, and is a member of a number of scientific societies such as the French Academy of Pharmacy, the Royal Academy of Medicine of Belgium, and the American Chemical Society. His recently granted Emeritus status has freed him from administrative duties and gives him more time for writing, editing and collaborating in research projects. His hobbies, interests, and passions include jogging, science fiction, epistemology, teaching, and scientific exploration.

© 2007 Elsevier Ltd. All Rights Reserved Comprehensive Medicinal Chemistry II

No part of this publication may be reproduced, stored in any retrieval system or transmitted ISBN (set): 0-08-044513-6 in any form by any means electronic, electrostatic, magnetic tape, mechanical, photocopying, recording or otherwise, without permission in writing from the publishers ISBN (Volume 5) 0-08-044518-7; pp. 1-9

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