Edited by R. Mannhold, H. Kubinyi, G. Folkers
Editorial Board
H. Buschmann, H. Timmerman, H. van de Waterbeemd, John Bondo Hansen
Erlanson, Daniel A. / Jahnke, Wolfgang (Eds.)
Fragment-based Drug Discovery
Lessons and Outlook
2015
ISBN: 978-3-527-33775-0
Vol. 67
Urbán, László / Patel, Vinod F. / Vaz, Roy J. (Eds.)
Antitargets and Drug Safety
2015
ISBN: 978-3-527-33511-4
Vol. 66
Keserü, György M. / Swinney, David C. (Eds.)
Kinetics and Thermodynamics of Drug Binding
2015
ISBN: 978-3-527-33582-4
Vol. 65
Pfannkuch, Friedlieb / Suter-Dick, Laura (Eds.)
Predictive Toxicology
From Vision to Reality
2014
ISBN: 978-3-527-33608-1
Vol. 64
Kirchmair, Johannes (Ed.)
Drug Metabolism Prediction
2014
ISBN: 978-3-527-33566-4
Vol. 63
Vela, José Miguel / Maldonado, Rafael / Hamon, Michel (Eds.)
In vivo Models for Drug Discovery
2014
ISBN: 978-3-527-33328-8
Vol. 62
Liras, Spiros / Bell, Andrew S. (Eds.)
Phosphodiesterases and Their Inhibitors
2014
ISBN: 978-3-527-33219-9
Vol. 61
Hanessian, Stephen (Ed.)
Natural Products in Medicinal Chemistry
2014
ISBN: 978-3-527-33218-2
Vol. 60
Lackey, Karen / Roth, Bruce (Eds.)
Medicinal Chemistry Approaches to Personalized Medicine
2013
ISBN: 978-3-527-33394-3
Vol. 59
Brown, Nathan (Ed.)
Scaffold Hopping in Medicinal Chemistry
2013
ISBN: 978-3-527-33364-6
Vol. 58
Hoffmann, Rémy / Gohier, Arnaud / Pospisil, Pavel (Eds.)
Data Mining in Drug Discovery
2013
ISBN: 978-3-527-32984-7
Vol. 57
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For my daughter Eva
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In drug discovery, a lead series is a series of related structures (hits or confirmed actives) that display a clear structure–activity relationship (SAR) versus the desired target but still exhibit suboptimal physicochemical, pharmacological, DMPK, toxicological, or intellectual-property-related attributes requiring further chemical modification to improve these liabilities and to deliver a clinical candidate. These chemical modifications most often aid to improve potency, selectivity, pharmacokinetic parameters, or physicochemical properties such as solubility.
Lead generation comprises five basic objectives [1]: (a) validation of structure and purity; (b) definition of a pharmacophore, as such information impacts the strategy for SAR development of the series; (c) selectivity enhancement in order to minimize activity at closely related molecular targets; (d) exclusion of compounds with inappropriate modes of action, such as nonspecific binding to the molecular target; and (e) increase of potency. While hits have often activities in the micromolar range, such compounds need to be optimized toward higher potency as they might be problematic later in development with respect to achieving effective concentrations in the target tissue or organ.
Lead generation [1–5] is the most critical stage in early drug discovery where small-molecule hits stemming from active generation methods are evaluated and undergo limited optimization to identify those promising leads, which then will be subject to more extensive optimization efforts in a subsequent step of drug discovery called lead optimization. Lead generation mainly defines the chemical structures of subsequent clinical candidates [6] and as such is of great importance for the success of a given project.
The drug discovery process generally follows the following path:
While traditionally the generation of actives has been performed either in analogy to endogenous ligands [7] or by high-throughput screening (HTS) [8], today the medicinal chemist has a wealth of different lead generation methods at hand and lead generation paradigms have changed and evolved constantly. This rather drastic change was the necessary consequence of high attrition rates in the clinic, the escalation of drug development costs beyond the billion dollar mark, and the ever higher expectations of safety and efficacy on the part of regulatory agencies, physicians, and patient populations at large. With an increasing emphasis on translational science and more relevant screening assays, requirements for lead generation chemists have constantly increased as well, difficult drug targets need to be mastered, and hits from phenotypic screens need to be converted into drugs to just name a few of these challenges.
How can a lead generation chemist of today then choose the right active generation methods? How many should be considered and when and what are their advantages and limitations? Which and how many compounds should be screened and which hits should be progressed? How should ancillary techniques like predictive methods, affinity measurements or lead matrices be considered and used? How can the so-called “undrugable” targets, for example, protein–protein interactions or phosphatases be mastered? How can a phenotypic screen outcome be converted into drugs? How can a lead generation chemist be sure that a lead series will be delivering a successful clinical candidate after undergoing the lead optimization phase? All these questions and many more will be discussed and answered in this book by a team of selected, highly experienced lead generation scientists, along with many practical examples of “real-life” learnings.
This volume is organized in six parts, the first of which introduces into the topic of this volume with “learnings from the past” by Mike Hann and an overview on “modern lead generation strategies” by Jörg Holenz, the editor of this volume, and Dean Brown.
In 15 well-elaborated chapters, the following four parts provide the reader with a comprehensive overview of the broad spectrum of methods and strategies currently applied in lead generation projects. The importance of target identification for generating successful leads (Chapters 3 and 4), the broad spectrum of evolving lead generation methods (Chapters 5–11), various approaches to convert hits to successful leads along with ancillary techniques (Chapters 12–16), as well as hypothesis-driven lead generation (Chapter 17) deserve particular mentioning in this context.
The last part exemplifies the above-mentioned methods and strategies in eight impressive success stories on lead structure discovery in many different areas, such as H3 antagonists, PAR-1 antagonists, inhaled ß2-receptor agonists, and cathepsin A inhibitors, or in projects for neglected diseases, to mention a few.
The series editors are grateful to Jörg Holenz for organizing this volume and to work with such excellent authors. Last but not least, we thank Frank Weinreich and Waltraud Wüst from Wiley-VCH Verlag GmbH for their valuable contributions to this project and to the entire book series.
DüsseldorfRaimund Mannhold
Weisenheim am SandHugo Kubinyi
ZürichGerd Folkers
January 2016
As drug discovery is fundamentally changing during recent years with an ever-growing emphasis on translation and more disease relevant screening assays, the borders between biology and chemistry become increasingly invisible: chemical biology-driven target identification and concurrent lead generation represent today standard follow-up methods for the increasing number of projects relying on phenotypic screening, while novel drug classes like antibody–drug conjugates close the gap between large biological and small chemical molecules. Today, medicinal chemists play a pivotal part in these multidisciplinary processes by leading and actively shaping them. Lead generation is the area where this evolution is most prominent and has affected a couple of major paradigm changes. It is a crucial discipline where structural properties and liabilities of chemical compounds are defined to a large degree, thus strongly influencing the potential for further optimization toward a successful candidate to test a clinical hypothesis. Lead generation represents one of the most important disciplines for project success, and “shortcuts” in lead generation are often penalized at later stages.
Starting my career in lead optimization and preclinical development, I worked in projects where lead optimization failed to deliver a candidate drug and a renewed lead generation effort was deemed necessary, leading to severe delays and failures to nominate a clinical candidate. This is how I started to gain interest in lead generation and in answering the question how to assure that lead optimization teams would get the lead series quality and choice they need to deliver a successful drug candidate without bigger delays. In the past 6 years, I immersed myself in the wonderful and fascinating world of lead generation. Like no other discipline, lead generation miraculously combines science with technology and creativity. The successful lead generation chemist of today truly works as a discoverer of hitherto unknown targets and at the same time as a creator of leads on the interface between medicinal chemistry and multiple rapidly evolving disciplines such as genetics, biology and pharmacology, or data visualization. Last but not least, she or he must be a “technique aficionado” to embrace all the fascinating ancillary technologies!
I tremendously enjoy working in lead generation and learning all about it, and out of this desire came the idea to write this book together with friends and colleagues from companies and academia, across diverse cultures and backgrounds, but united in the same passion and expertise for this discipline. The book took about 3 years from concept to completion, and I am especially proud to have worked with such a distinguished team of lead generation experts. In my personal view, there is a clear need for an up-to-date reference book covering all aspects of modern applied lead generation. It is my sincere hope that this book may fill this gap and provide a comprehensive answer to “everything you always wanted to know about lead generation!”
I would like to thank the authors for their fantastic contributions and for patiently accommodating all my feedback, the series editors for their trust in me and my concept, the Wiley-VCH team around Frank Weinreich and Waltraud Wüst for the production of this book, and finally my family for being patient with me, when I was spending far too much time on this book than I should as a husband and father.
Cambridge (MA)Jörg Holenz
November 2015