The Handbook of Medicinal Chemistry
Preface to the First Edition
Published:03 Feb 2023
2023. "Preface to the First Edition", The Handbook of Medicinal Chemistry, Simon E Ward, Andrew Davis
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Medicinal Chemistry sits at the heart of the pharmaceutical industry and the medicinal chemist has one of the most challenging and rewarding jobs imaginable. The medicinal chemist designs the drug which must balance often conflicting demands of a suitable dose, by the chosen delivery route, at a desired dose frequency to provide a therapeutic effect while maintaining margins to adverse effects throughout the dosing period. The drug molecule may be given to millions of patients all of whom may respond to the drug differently, and all of whom must be treated safely and effectively. Whilst drug discovery is undoubtedly an endeavour involving a wide range of scientific disciplines, the medicinal chemists are critical to the design and progression of a drug molecule. It is the medicinal chemist who integrates and balances the diverse inputs into a single chemical structure which has the potential to become a new medicine.
This is an enormously difficult task. Our advances in synthetic organic chemistry mean that we can respond well to the challenges of preparing and purifying new molecules and chemists can be trained in these skills during undergraduate and graduate studies. In contrast, compound design is far harder to control and requires extensive experience and knowledge to take the sometimes subjective decisions to arrive at a potential drug candidate. There are few universal rules in drug design, and barely any universally accepted guidelines, and it sometimes seems success is more a matter of chance. But, as Louis Pasteur said, “chance favours the prepared mind”. However, given the current challenges and high attrition during the development phase, and the acceptance that many reasons for failure are directly attributable to the chemical structure of the drug candidate, medicinal chemists have a duty to design the best molecule possible to advance from research into development and beyond.
The aim of this book, through a series of monographs by leading scientists from across the world, from major pharmaceutical companies, biotechnology companies, contract research organisations and academia is to prepare the medicinal chemist to spot the good chances.
The book covers the whole R&D process from target validation through to late stage clinical trials, through descriptions of the background science, the process, learnings, case studies, leading references and even hints and tips.
The foreword has been written by one of our industry's most respected scientists, Simon Campbell CBE FRS, FMedSci. Simon Campbell joined Pfizer as a Medicinal Chemist in 1972, and was a key member of the teams that led to such blockbuster drugs as Cardura, Norvasc and Viagra. He went on to become Pfizer's Senior Vice President for World-wide Drug Discovery and Medicinal R&D in Europe. He was President of the Royal Society of Chemistry from 2004 to 2006 and maintains a very active and influential role in our industry. With his considerable experience Simon provides us with his personal learnings, and the undoubted opportunities for medicinal chemistry looking forward.
The early chapters describe the tools of the medicinal chemist's trade such as physical organic chemistry, computational chemistry and QSAR, library design, fragment based lead generation and structure based design.
The middle section of the book covers the supporting scientific disciplines, including assay development, receptor pharmacology and in vivo model development, drug metabolism and pharmacokinetics, molecular biology, toxicology and translational science, computational biology and of critical importance, intellectual property.
The later sections of the book describe the overall research and development process from target generation, lead identification and optimisation through to pharmaceutical development, clinical development and chemical development, including the importance of efficient project management.
Due to the high levels of failure faced during drug development, case studies of successful R&D are hard to find, but are invaluable as a touchstone for pathways to success. So the last three chapters provide case studies of drugs that made it into the later stages of clinical development and/or onto the market, Brilinta, Aleglitazar and Lapatinib. Even during the preparation of this book, one of our case studies was unfortunately halted during Phase III trials. As sad as Phase III failure is, few drugs reach this stage of clinical development and there are many lessons to be learnt in this story that justify its esteemed place in this section.
The book began as life as a proposal to update to a 3rd edition the Royal Society of Chemistry's long running publication “Principles and Practice of Medicinal Chemistry”. The first edition was published over 20 years ago, and was a spin-out from the biannual Royal Society of Chemistry Medicinal Chemistry Summer Workshop, which itself has been running for over 40 years and has been the training ground for many of our industry's leading medicinal chemists. The 3rd edition proposal retained some distinctive features of its predecessors, being highly practitioner focused, but grew to incorporate a broader context and to reflect the changing reader demographic reflected in the changing industry and drug discovery environments. It also grew to incorporate new opportunities that did not exist 20 years ago.
Paper publishing is as valid today as it has ever been, but mobile computing and e-publishing are changing the way information can be used and presented. E-publications allow interaction with the content which cannot occur with paper. App-stores allow easy access to sophisticated software that can be delivered and updated with ease. Many tools potentially useful to medicinal chemists do not exist in an easily accessible and secure manner. So for the 3rd edition we wanted to develop, as a companion to the print book, a set of useful medicinal chemistry apps to run locally on tablet computers, and also a fully interactive e-book version to complement the paper copy. The apps would bring to life concepts described within the book chapters and allow chemists to quickly and easily find help in their design challenges.
While even 10 years ago protein structure visualisation and small molecule modelling required high-end workstations and costly software, nowadays this can be accomplished on a tablet computer. Indeed, the frontispiece image of this book was designed inside the freeware app iMolview from Molsoft on an Apple iPad3. Similarly static pictures of X-ray crystal structures within the chapters can be brought into high resolution reality, and the reader can interact with the exact data that the original medicinal chemist used in the documented design. Structures can link to ChemSpider or even Wikipedia and other online resources providing deeper context, and hyperlinks to regulatory guidance mean the medicinal chemist has access to primary information sources relevant to each chapter.
So while this 3rd edition was inspired by its predecessors, with the companion apps and the e-book format, it was time to change the book's name. We hoped the book would become an everyday companion for the practicing medicinal chemist, and so the title “Handbook of Medicinal Chemistry” seemed appropriate. With both print and electronic format and companion apps we hope that, with this handbook, we can more fully prepare the mind of the medicinal chemist to pick the right chances.
Andrew Davis and Simon E Ward