Designing Multi-Target Drugs: Rsc (RSC Drug Discovery, Band 21) - Hardcover

Hardcover

ISBN 10: 1849733627 ISBN 13: 9781849733625

Verlag: ROYAL SOCIETY OF CHEMISTRY, 2012

Inhaltsangabe

Multi-target drug discovery (MTDD) is an emerging area of increasing interest to the drug discovery community. Drugs that modulate several targets have the potential for an improved balance of efficacy and safety compared to single targets agents. Although there are a number of marketed drugs that are thought to derive their therapeutic benefit by virtue of interacting with multiple targets, the majority of these were discovered accidentally. Written by world renowned experts, this is the first book to gather together knowledge and experiences of the rational discovery of multi-target drugs. It describes the current state of the art, the achievements and the challenges of the field and importantly the lessons learned by researchers to date and their application to future MTDD.

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Über die Autorinnen und Autoren

Richard Morphy gained his BSc (1995) and PhD (1989; supervisor: Prof. David Parker) in Chemistry from University of Durham 1989-1995: Medicinal chemist at Celltech, Slough, UK working on oncology and inflammation projects 1995-to date: Section head / Senior Research Fellow at Organon/SPRI/MSD, Newhouse, Scotland working on CNS and CV projects. He has an extensive track record of research, publications and presentations in the area of multi-target drug discovery (MTDD). John Harris gained his BSc.(Chemistry, 1999) from University of Exeter; PhD (Chemistry, 1974) from Queen Mary College, University of London (Supervisor: Prof. B.C.L. Weedon FRS) Postdoc study 1973-1975 with Prof. C.W.Rees at University of Liverpool. 1975 - 1982 Medicinal Chemist at Wellcome Labs, Beckenham, working on cardiovascular projects. 1983-1988 Principal Scientist 1989 - 1995 Head of Cardiovascular Area, Wellcome UK. 1996 - 2008 Founder and CSO of BioFocus (now division of Galapagos); 2009 - to date, independent pharma/biotech consultant. Comprehensive track record of research, publications and presentations in the areas of enzyme inhibitors, prostaglandins, compound library design, kinase drug development in oncology, inflammation and CNS, and multi-targeted drug discovery.

Richard Morphy gained his BSc (1995) and PhD (1989; supervisor: Prof. David Parker) in Chemistry from University of Durham 1989-1995: Medicinal chemist at Celltech, Slough, UK working on oncology and inflammation projects 1995-to date: Section head / Senior Research Fellow at Organon/SPRI/MSD, Newhouse, Scotland working on CNS and CV projects. He has an extensive track record of research, publications and presentations in the area of multi-target drug discovery (MTDD). John Harris gained his BSc.(Chemistry, 1999) from University of Exeter; PhD (Chemistry, 1974) from Queen Mary College, University of London (Supervisor: Prof. B.C.L. Weedon FRS) Postdoc study 1973-1975 with Prof. C.W.Rees at University of Liverpool. 1975 - 1982 Medicinal Chemist at Wellcome Labs, Beckenham, working on cardiovascular projects. 1983-1988 Principal Scientist 1989 - 1995 Head of Cardiovascular Area, Wellcome UK. 1996 - 2008 Founder and CSO of BioFocus (now division of Galapagos); 2009 - to date, independent pharma/biotech consultant. Comprehensive track record of research, publications and presentations in the areas of enzyme inhibitors, prostaglandins, compound library design, kinase drug development in oncology, inflammation and CNS, and multi-targeted drug discovery.

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This book is intended to provide an integrated and comprehensive overview of modern approaches to multi-target drug discovery (MTDD) and the state of our knowledge in the over-arching field of polypharmacology. Given the intense current interest in this field, the editors hope that the book will be of significant interest to medicinal and computational chemists in the commercial sector and in academia, as well as the wider drug discovery community. Many readers will already be aware of the serendipitous nature of the discovery of many existing multi-target drugs. In this book the editors focus on the rational and practical execution of MTDD. The chapters are written by widely recognized experts and opinion leaders in the field. The first challenge of MTDD is to identify biologically validated combinations of targets relevant to a disease state. However it is equally important that these disease relevant combinations are chemically tractable from a medicinal chemistry perspective. The book thus follows a natural thread from target identification and validation, through lead generation and lead optimisation, and finally to clinical development. A key feature of the book is a collection of seminal case studies chosen to illustrate the challenges and opportunities of MTDD. These include compounds at various stages of development from pre-clinical to marketed drugs.

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Designing Multi-Target Drugs

By J. Richard Morphy, C. John Harris

The Royal Society of Chemistry

Copyright © 2012 Royal Society of Chemistry
All rights reserved.

ISBN: 978-1-84973-362-5

Contents

Chapter 1 Simple Drugs Do Not Cure Complex Diseases: The Need for Multi-Targeted Drugs Jorrit J. Hornberg, 1, 
Chapter 2 Clinical Need and Rationale for Multi-Target Drugs in Psychiatry Mohammed Shahid, 14, 
Chapter 3 Drug Molecules and Biology: Network and Systems Aspects Malcolm P. Young, Steven Zimmer and Alan V. Whitmore, 32, 
Chapter 4 Chemoinformatic Approaches to Target Identification Elisabet Gregori-Puigjané and Michael J. Keiser, 50, 
Chapter 5 Designing Multi-Target Drugs: In Vitro Panel Screening – Biological Fingerprinting Jonathan S. Mason, 66, 
Chapter 6 Phenotypic and In Vivo Screening: Lead Discovery and Drug Repurposing Christopher A. Lipinski, 86, 
Chapter 7 Target/s Identification Approaches – Experimental Biological Approaches Giulio Superti-Furga, Kilian Huber and Georg Winter, 94, 
Chapter 8 Historical Strategies for Lead Generation J. Richard Morphy, 111, 
Chapter 9 In Silico Lead Generation Approaches in Multi-Target Drug Discovery Xiaohou Ma and Yuzong Chen, 130, 
Chapter 10 The Challenges of Multi-Target Lead Optimization J. Richard Morphy, 141, 
Chapter 11 Combination Agents Versus Multi-Targeted Agents – Pros and Cons Jose G. Monzon and Janet Dancey, 155, 
Chapter 12 The Discovery of Lapatinib Karen E. Lackey, 181, 
Chapter 13 Identification and Optimization of Dual PI3K/mTOR Inhibitors Andreas Karlsson and Carlos García-Echeverría, 206, 
Chapter 14 Discovery of HDAC-Inhibiting Multi-Target Inhibitors Xiong Cai and Changgeng Qian, 221, 
Chapter 15 Targeting Protein–Protein Interactions: Dual Inhibitors of Bcl-2 and Bcl-xL Michael D. Wendt, 243, 
Chapter 16 Discovery of the Anti-Psychotic Drug, Ziprasidone John A. Lowe, III, 263, 
Chapter 17 The Rational Design of Triple Reuptake Inhibitors for the Treatment of Depression Robert J. Weikert, 270, 
Chapter 18 Discovery of Multi-Target Agents for Neurological Diseases via Ligand Design Maria Laura Bolognesi, Carlo Melchiorre, Cornelis J. Van der Schyf and Moussa Youdim, 290, 
Chapter 19 Designing Drugs with Dual Activity: Novel Dual Angiotensin II and Endothelin Receptor Antagonists Natesan Murugesan, 316, 
Chapter 20 Ethyl Urea Inhibitors of the Bacterial Type II Topoisomerases DNA Gyrase (GyrB) and Topoisomerase IV (ParE) Stephen P. East, Lloyd G. Czaplewski and David J. Haydon, 335, 
Epilogue, 353, 
Subject Index, 356, 

CHAPTER 1

Simple Drugs Do Not Cure Complex Diseases: The Need for Multi-Targeted Drugs

JORRIT J. HORNBERG

H Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark

Email: JJH@Lundbeck.com

1.1 Introduction

The contents of this book provide a comprehensive overview of the field of polypharmacology and modern approaches to identify drugs that hit multiple targets, including a number of case studies. But why do we actually need such multi-targeted drugs? This introductory chapter aims to answer that question. First, there is clearly a need for better and safer drugs in the clinic and also to improve output (productivity) of drug discovery and development in general. Second, many diseases with unmet medical needs are in essence complex and multi-factorial. I will discuss two disease areas, cancer and rheumatoid arthritis, to exemplify this complexity. Systems biology and network control analysis have shown that the systems underlying complex diseases are robust against perturbations and are always controlled by more than one biochemical process. Therefore, aiming to hit multiple targets is a better strategy than to hit a single target. Finally, though polypharmacology is naturally associated with toxicology and off-target side effects, it can be argued that multi-targeted drugs, when rationally designed, can actually have a larger therapeutic window than those hitting a single target and thus prove to be safer drugs.

1.2 The Need for Better and Safer Drugs

There are two main reasons why we need better and safer drugs.

Firstly, there is the unmet medical need in the clinic. Patients need safe cures and complex diseases are difficult to cure. Cancer survival rates, for example, are still lower than desired, roughly 50–65% in Europe and the US, making it a leading cause of death, responsible for almost 25% of all deaths in the US. Other examples include autoimmune disorders, some cardiovascular diseases, diabetes and neurodegenerative diseases. The incidence of some of these diseases is expected to increase with the increasingly ageing population. Dementia, for instance, affects almost 1% of those at 60–64 years of age and that number doubles for each subsequent 5-year cohort to 25–33% of those ≥ 85 years of age. Furthermore, the incidence of serious adverse drug reactions in hospitalized patients is so high that it ranks as the 4th–6th leading cause of death.

Secondly, the low success rate of drug development calls for better and safer drugs. In the past few years, an average of only ~20 new drugs were approved annually. This is the result of the high attrition rates in clinical development: about 90% of all new drugs fail after first-in-human testing, varying from 80% for cardiovascular diseases to 95% for cancer. The main underlying causes were identified to be lack of efficacy and poor safety (toxicology and clinical safety), each accounting for ~30% of all failures.

One may therefore argue that we need to hit better targets. However, going after novel targets has, in itself, not proven to be a particularly successful strategy for drug development. Attrition of candidates with a novel mechanism of action is higher than average. In addition, many diseases with unmet medical needs are complex and multi-factorial. Therefore, an approach to hit multiple targets may be more successful. The next two sections of this chapter discuss the complexity of cancer and rheumatoid arthritis.

1.3 Cancer

Two decades ago, Fearon and Vogelstein proposed their genetic model for colorectal tumorigenesis. From comparing cells from multiple stages of colorectal cancer, it became apparent that, at each stage, cells had acquired at least one additional mutation, compared to the previous stage. The fact that carcinogenesis is a multi-step process requiring multiple sequential mutations has since been confirmed many times, e.g. by similar models for other types of cancer and by the artificial creation of tumour cells by introducing defined genetic alterations. Besides mutations that change the structure and function of a gene product, (epi)genetic alterations which influence gene expression also contribute to carcinogenesis, such as gene amplification, changes in DNA methylation and histone acetylation, and the functioning of micro-RNAs. The list of genes which are causally implicated in cancer via genetic alteration currently contains 436 genes. Though some genes are frequently mutated in many cancer types, it is rather a combination of low frequency mutations that drive the cancer phenotype and they differ per cancer type. This (epi)genetic heterogeneity of cancer presents a major challenge. Disturbances of the signal transduction pathways in which most of these cancer genes function leads to the so-called 'hallmarks of cancer', including evasion of apoptosis and growth control, self-sufficiency in growth signals,...

Details zur Ausgabe

• Verlag: ROYAL SOCIETY OF CHEMISTRY
• Erscheinungsdatum: 2012
• Sprache: Englisch
• ISBN 10: 1849733627
• ISBN 13: 9781849733625
• Einband: Gebundene Ausgabe
• Anzahl der Seiten: 365
• Herausgeber: Morphy J. Richard, Harris C. John
• Kontakt zum Hersteller: Nicht verfügbar
• Verantwortliche Person: Nicht verfügbar