Preface

Small molecules constitute the most versatile modality in drug discovery since they can be designed by medicinal chemists to be amenable to all routes of administration and to reach any tissue within the body. With the introduction of early absorption, distribution, metabolism, excretion and toxicity (ADMET) profiling later-stage failures due to inadequate pharmacokinetics and a number of previously dreaded safety liabilities could be markedly reduced. During the last two to three decades an impressive body of knowledge has been accumulated on design strategies and tactics to solve common ADMET issues, which have been collected and diligently summarized in this handbook by a distinguished global group of experienced medicinal chemists and ADMET experts across academia and the pharmaceutical industry.

Medicinal chemistry experience and knowledge of how best to modify molecular structure to solve ADMET issues is difficult and tedious to retrieve from the literature, public databases and even corporate data warehouses. The Medicinal Chemist's Guide to Solving ADMET Challenges addresses this gap by presenting the most proven strategies to solve challenges associated with a comprehensive set of ADMET parameters which are commonly subject to medicinal chemistry optimization. These tactics are exemplified with a curated collection of concrete examples displayed in a highly visual “table-of-contents” style format, allowing readers to rapidly identify the most promising approaches applicable to their own challenges.

Each chapter of this handbook is dedicated to a single or a group of related ADMET properties. The sections summarizing the mitigation strategies and the examples are preceded by a concise yet comprehensive introduction of the parameter. This comprises a discussion of the relevance of the parameter, a description of state-of-the-art screening strategies including key assays and in silico prediction methods, structural and mechanistic aspects and, for enzymes and transporters, an overview of the protein family, expression, activity and substrates. A major remit is to point readers who would like to learn about some of these aspects in more detail to high-quality literature sources. Out of these around half a dozen key references are highlighted in a box, visually offsetting the discussion and exemplification of mitigation strategies from the introductory part.

The unique and uniform format of the chapters of this handbook is in part inspired by Wikipedia, which provides a quick and concise overview of a topic while providing links and references for further reading. Wikipedia is also a source of knowledge about ADMET properties, however, on a more superficial level and generally lacking information on mitigation strategies. Yet there is a great tradition of hugely popular and useful printed reference works on finding solutions which many chemists like to have at their fingertips, such as Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts or Jerry March's Advanced Organic Chemistry. In the field of small molecule drug discovery, The Handbook of Medicinal Chemistry edited by Andrew Davis and Simon E. Ward has become a landmark oeuvre, which encyclopedically covers the entire R&D process. The Medicinal Chemist's Guide to Solving ADMET Challenges is meant to complement the latter by compendiously providing medicinal chemistry practitioners and drug discovery scientists across small and large pharmaceutical companies as well as students interested in entering the field with answers and solutions to their daily challenges pertaining to the universal task of optimizing ADMET properties in search of candidate drugs with a well-balanced overall profile.

I would like to conclude by giving my sincere thanks to all chapter authors for their outstanding work and dedication to bringing this handbook to a successful completion. Furthermore, I would also like to extend my thanks to Alexander Mayweg and Andrew Thomas for their key roles and support in the inception of this book. Last but not least my special thanks go to Sarah Skerratt for her enthusiasm and invaluable contributions to the initiation of this project.

Patrick Schnider