Antitargets and Drug Safety E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 1022

Veröffentlichungsjahr: 2015

Beschreibung

With its focus on emerging concerns of kinase and GPCR-mediated antitarget effects, this vital reference for drug developers addresses one of the hot topics in drug safety now and in future.
Divided into three major parts, the first section deals with novel technologies and includes the utility of adverse event reports to drug discovery, the translational aspects of preclinical safety findings, broader computational prediction of drug side-effects, and a description of the serotonergic system. The main part of the book looks at some of the most common antitarget-mediated side effects, focusing on hepatotoxicity in drug safety, cardiovascular toxicity and signaling effects via kinase and GPCR anti-targets. In the final section, several case studies of recently developed drugs illustrate how to prevent anti-target effects and how big pharma deals with them if they occur. The more recent field of systems pharmacology has gained prominence and this is reflected in chapters dedicated to the utility in deciphering and modeling anti-targets. The final chapter is concerned with those compounds that inadvertently elicit CNS mediated adverse events, including a pragmatic description of ways to mitigate these types of safety risks.
Written as a companion to the successful book on antitargets by Vaz and Klabunde, this new volume focuses on recent progress and new classes, methods and case studies that were not previously covered.

Leseprobe

CONTENTS

Cover

Related Titles

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Section 1: General Concept for Target-based Safety Assessment

Chapter 1: Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance

1.1 Introduction

1.2 Postmarketing Pharmacovigilance

1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs

References

Chapter 2: In Silico Prediction of Drug Side Effects

2.1 Large-Scale Prediction of Drug Activity

2.2 Multiscale Models of Adverse Drug Reactions

References

Chapter 3: Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets

3.1 Introduction

3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA)

3.3 Data Interpretation: Modifying Factors

3.4 Conclusions

References

Chapter 4: Pathological Conditions Associated with the Disturbance of the 5-HT System

4.1 Introduction

4.2 From “St. Anthony's Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology

4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers

4.4 Gastrointestinal and Antiemetic Indications, the 5-HT

3

/5-HT

4

Receptor Links

4.5 Antipsychotics and the 5-HT

2

/Dopamine D

2

Link (and Many Other 5-HT Receptors)

4.6 Antimigraine Medications of Old and New and the 5-HT

1B/1D

Receptors

4.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters

4.8 Conclusions

References

Section 2: Hepatic Side Effects

Chapter 5: Drug-Induced Liver Injury: Clinical and Diagnostic Aspects

5.1 Introduction

5.2 Special Problems of Postmarketing Hepatotoxicity

5.3 Special Problems for New Drug Development

5.4 Closing Considerations

References

Chapter 6: Mechanistic Safety Biomarkers for Drug-Induced Liver Injury

6.1 Introduction

6.2 Drug-Induced Toxicity and the Liver

6.3 Current Status of Biomarkers for the Assessment of DILI

6.4 Novel Investigational Biomarkers for DILI

6.5 Conclusions and Future Perspectives

References

Chapter 7: In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery

7.1 Introduction

7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants

7.3 Models to Mitigate Hepatocyte Dedifferentiation

7.4 Understanding Immune-Mediated Hepatotoxicity

7.5 Conclusions

References

Chapter 8: Transporters in the Liver

8.1 Introduction

8.2 Role of Organic Anion Transporters for Drug Uptake

8.3 Drug Interaction with the Bile Salt Export Pump

8.4 Susceptibility Factors for Drug–BSEP Interactions

8.5 Role of BSEP in Drug Development

References

Chapter 9: Mechanistic Modeling of Drug-Induced Liver Injury (DILI)

9.1 Introduction

9.2 Mechanistic Modules in DILIsym® version 3A

9.3 Examples of Bile Acid-Mediated Toxicity Module

9.4 Conclusions and Future Directions

References

Section 3: Cardiovascular Side Effects

Chapter 10: Functional Cardiac Safety Evaluation of Novel Therapeutics

10.1 Introduction: What Is the Issue?

10.2 Cardiac Function: Definitions and General Principles

10.3 Methods Available to Assess Cardiac Function

10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans?

10.5 Risk Assessment

10.6 Summary, Recommendations, and Conclusions

References

Chapter 11: Safety Aspects of the Ca

v

1.2 Channel

11.1 Introduction

11.2 Structure of Ca

v

1.2 Channels

11.3 Function of Ca

v

1.2 Channels in Cardiac Tissue

11.4 Pharmacology of Ca

v

1.2 Channels: Translation to the Clinic

11.5 Prediction of Ca

v

1.2 Off-Target Liability

References

Chapter 12: Cardiac Sodium Current (Na

v

1.5)

12.1 Background and Scope

12.2 Structure and Function

12.3 Physiological Role and Drug Actions

12.4 Methodology

12.5 Translation of Effects on

I

NaF

: Relation to Conduction Velocity and Proarrhythmia

12.6 Conclusions

References

Chapter 13: Circulating Biomarkers for Drug-Induced Cardiotoxicity: Reverse Translation from Patients to Nonclinical Species

13.1 Introduction

13.2 Cardiac Troponins

13.3 Natriuretic Peptides

13.4 Novel/Exploratory Biomarkers: H-FABP, miRNA, and Genomic Biomarkers

13.5 Regulatory Perspective

13.6 Conclusions and Future Perspectives

References

Chapter 14: The Mechanistic Basis of hERG Blockade and the Proarrhythmic Effects Thereof

14.1 Introduction

References

Section 4: Kinase Antitargets

Chapter 15: Introduction to Kinase Antitargets

References

Chapter 16: Clinical and Nonclinical Adverse Effects of Kinase Inhibitors

16.1 Introduction

16.2 Perspectives on the Clinical Safety of Kinase Inhibitor Therapy

16.3 Adverse Effects of Kinase Inhibitor Drugs

16.4 Derisking Strategies for Kinase Inhibitor Toxicity

16.5 Concluding Remarks

References

Chapter 17: Cardiac Side Effects Associated with Kinase Proteins and Their Signaling Pathways

17.1 A Case Study

17.2 Introduction

17.3 Cardiac-Specific Kinase Antitargets

17.4 Current and Future Directions

17.5 Conclusions

References

Chapter 18: Case Studies: Selective Inhibitors of Protein Kinases – Exploiting Demure Features

18.1 Introduction

18.2 Case I: Indane Oximes as Selective B-Raf Inhibitors [26]

18.3 Case II: ARRY-380 (ONT-380) – an ErbB2 Agent that Spares EGFR [45]

18.4 Case III: Discovery of GDC-0068 (Ipatasertib), a Potent and Selective ATP-Competitive Inhibitor of AKT [58]

18.5 Concluding Remarks

References

Section 5: Examples of Clinical Translation

Chapter 19: Torcetrapib and Dalcetrapib Safety: Relevance of Preclinical In Vitro and In Vivo Models

19.1 Introduction

19.2 Effect of Torcetrapib on Blood Pressure

19.3

In Vitro

Studies

19.4

In Vivo

Studies

19.5 General Safety Risk with Increased Aldosterone and BP

19.6 Relevance of BP and Aldosterone Preclinical Models to Clinical Observation with Dalcetrapib and Anacetrapib

19.7 Similarities between Potent CETPi and Halogenated Hydrocarbons

19.8 Conclusions

References

Chapter 20: Targets Associated with Drug-Related Suicidal Ideation and Behavior

20.1 Introduction

20.2 Targets Associated with Increased Suicidal Intent and Behavior

20.3 Conclusions

References

Index

EULA

List of Tables

Table 1.1

Table 1.2

Table 1.3

Table 2.1

Table 2.2

Table 3.1

Table 6.1

Table 7.1

Table 7.2

Table 7.3

Table 9.1

Table 9.2

Table 9.3

Table 13.1

Table 13.2

Table 14.1

Table 14.2

Table 15.1

Table 15.2

Table 15.3

Table 15.4

Table 15.5

Table 15.6

Table 16.1

Table 18.1

Table 18.2

Table 18.3

Table 18.4

Table 18.5

Table 20.1

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 1.4

Figure 2.1

Figure 2.2

Figure 3.1

Figure 3.2

Figure 3.3

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 5.5

Figure 5.6

Figure 5.7

Figure 5.8

Figure 6.1

Figure 7.1

Figure 7.2

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 10.12

Figure 10.13

Figure 11.1

Figure 14.1

Figure 14.2

Figure 14.3

Figure 14.4

Figure 14.5

Figure 14.6

Figure 14.7

Figure 14.8

Figure 14.9

Figure 14.10

Figure 14.11

Figure 14.12

Figure 16.1

Figure 16.2

Figure 17.1

Figure 17.2

Figure 18.1

Figure 18.2

Figure 18.3

Figure 18.4

Figure 18.5

Figure 18.6

Figure 18.7

Figure 18.8

Figure 19.1

Figure 19.2

Figure 19.3

Figure 19.4

Figure 20.1

Figure 20.2

Figure 20.3

Guide

Cover

Table of Contents

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Related Titles

Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Kubinyi, G. Folkers

Editorial Board

H. Buschmann, H. Timmerman, H. van de Waterbeemd

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Vol. 55

Antitargets and Drug Safety

Edited by László Urbán, Vinod F. Patel, and Roy J. Vaz

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List of Contributors

Daniel J. Antoine

University of Liverpool

Institute of Translational Medicine

Department of Molecular and Clinical Pharmacology

MRC Centre for Drug Safety Science

Liverpool L69 3GE

UK

Richard J. Brennan

Sanofi US

Preclinical Safety

DSAR

153 2nd Ave.

Waltham, MA 02451

USA

Kim L.R. Brouwer

The University of North Carolina at Chapel Hill

UNC Eshelman School of Pharmacy

Division of Pharmacotherapy and Experimental Therapeutics

Chapel Hill, NC 27599

USA

José S. Duca

Novartis Institutes for BioMedical Research

Computer Assisted Drug Discovery

100 Technology Square

Cambridge, MA 02139

USA

Berengere Dumotier

Novartis Institutes for BioMedical Research

Preclinical Safety/Cardiac Electrophysiology

Klybeckstrasse 141, WKL.136.178

4057 Basel

Switzerland

Gül Erdemli

Novartis Institutes for BioMedical Research

Center for Proteomic Chemistry

Ion Channel Group

250 Massachusetts Ave.

Cambridge, MA 02139

USA

Ramy Farid

Schrödinger, Inc.

120 West Forty-Fifth Street, 17th Floor

New York, NY 10036

USA

Alexander Fekete

Novartis Institutes for BioMedical Research

Preclinical Safety

Preclinical Secondary Pharmacology

250 Massachusetts Avenue

Cambridge, MA 02139

USA

Oliver Flint

Bristol-Myers Squibb

Pharmaceutical Candidate

Optimization

Discovery Toxicology

Liberty Drive

Newtown, PA 18940

USA

Gary Gintant

AbbVie

Integrated Science and Technology

Department of Integrative Pharmacology

Abbott Park Road

Abbott Park, IL 60064

USA

Andrea Greiter-Wilke

F. Hoffmann-La Roche Ltd.

Pharmaceuticals/Metabolic DTA

Grenzacherstrasse 124

4070 Basel

Switzerland

Brian Guth

Boehringer Ingelheim Pharma GmbH & Co. KG

General Pharmacology, Drug Discovery Support

Biberach an der Riss

Germany

Robert L. Hamlin

QTest Labs LLC and The Ohio State University

1900 Coffey Road

Columbus, OH 43210

USA

Jacques Hamon

Novartis Institutes for BioMedical Research

Preclinical Safety Profiling

Klybeckstrasse 141

4057 Basel

Switzerland

Andreas Hartmann

Novartis Institutes for BioMedical Research

Preclinical Safety

Klybeckstrasse

4057 Basel

Switzerland

Brett A. Howell

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Daniel Hoyer

The University of Melbourne

Faculty of Medicine, Dentistry and Health Sciences

School of Medicine

Department of Pharmacology and Therapeutics

Parkville, Victoria 3010

Australia

and

The University of Melbourne

The Florey Institute of Neuroscience and Mental Health

30 Royal Parade

Parkville, Victoria 3052

Australia

and

The Scripps Research Institute

Department of Chemical Physiology

10550 North Torrey Pines Road

La Jolla, CA 92037

USA

Qi-Ying Hu

Novartis Institutes for BioMedical Research

Global Discovery Chemistry

100 Technology Square

Cambridge, MA 02139

USA

Haisong Ju

Novartis Institutes for BioMedical Research Head

Safety Pharmacology-US/Preclinical Safety

Novartis Pharmaceuticals Corporation

One Health Plaza

East Hanover, NJ 07936-1080

USA

Michael J. Keiser

University of California, San Francisco

Department of Pharmaceutical Chemistry

1700 4th Street

San Francisco, CA 94158

USA

and

University of California, San Francisco

Department of Bioengineering and

Therapeutic Sciences

1700 4th Street

San Francisco, CA 94158

USA

and

University of California, San Francisco

Institute for Neurodegenerative Diseases

675 Nelson Rising Lane

San Francisco, CA 94158

USA

Douglas A. Keller

Sanofi US

Preclinical Safety

DSAR

55 Corporate Dr.

Bridgewater, NJ 08807

USA

Gerd A. Kullak-Ublick

University Hospital Zurich

Department of Clinical Pharmacology and Toxicology

Raemistrasse 100

8091 Zurich

Switzerland

Pierre Lainée

Sanofi

DSAR 371, RUE DU PROF JOSEPH BLAYAC

Montpellier 34184

France

Ellen R. Laird

Array BioPharma Inc.

Computational Chemistry

3200 Walnut Street

Boulder, CO 80301

USA

Karen L. Leach

Pfizer

Centers for Therapeutic Innovation

3 Blackfan Circle

Boston, MA 02115

USA

Eugen Lounkine

Novartis Institutes for BioMedical Research

Center for Proteomic Chemistry

In Silico Lead Discovery

250 Massachusetts Avenue

Cambridge, MA 02139

USA

K. Andrew MacCannell

Novartis Institutes for BioMedical Research

100 Technology Square

Cambridge, MA 02139

USA

Mateusz Maciejewski

Novartis Institutes for BioMedical Research

Center for Proteomic Chemistry

Preclinical Safety Profiling

250 Massachusetts Avenue

Cambridge, MA 02139

USA

Frederic Moulin

Bristol-Myers Squibb

Pharmaceutical Candidate Optimization

Discovery Toxicology

Clover Lane

Madison, CT 06443

USA

Lutz Müller

F. Hoffmann-La Roche Ltd.

Pharmaceuticals/Metabolic DTA

Grenzacherstrasse 124

4070 Basel

Switzerland

Patrick Y. Müller

Novartis Pharma

Global Pharma Development Strategy

Fabrikstrasse

4057 Basel

Switzerland

Mark C. Munson

Sanofi US

LGCR-Boston Hub

153 2nd Ave

Waltham, MA, 02451

USA

Eric J. Niesor

F. Hoffmann-La Roche Ltd.

Pharmaceuticals/Metabolic DTA

Grenzacherstrasse 124

4070 Basel

Switzerland

Vinod F. Patel

Sanofi US

LGCR – Boston Hub

153 Second Avenue

Waltham, MA 02451

USA

Robert A. Pearlstein

Novartis Institutes for BioMedical Research

Computer Assisted Drug Discovery

100 Technology Square

Cambridge, MA 02139

USA

Sarita Pereira1)

Novartis Institutes for BioMedical Research

250 Massachusetts Avenue

Cambridge, MA 02139

USA

Dusty Sarazan

Data Sciences International

119 14th Street NW, Suite 100

St. Paul, MN 55112

USA

John R. Senior

Food and Drug Administration

Center for Drug Evaluation and Research

Office of Surveillance and Epidemiology

Office of Pharmacovigilance and Epidemiology

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

USA

Lisl K. Shoda

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Scott Q. Siler

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Matt Skinner

AstraZeneca R&D

Drug Safety and Metabolism

Alderley Park

Macclesfield SK10 4TG

UK

Bruno Stieger

University Hospital Zurich

Department of Clinical Pharmacology and Toxicology

Raemistrasse 100

8091 Zurich

Switzerland

Martin Traebert

Novartis Institutes for BioMedical Research

Preclinical Safety/Cardiac Electrophysiology

Klybeckstrasse 141, WKL.136.178

4057 Basel

Switzerland

Christian Trendelenburg

Novartis Institutes for BioMedical Research

Preclinical Safety

Klybeckstrasse 141,

4057 Basel

Switzerland

László Urbán

Novartis Institutes for BioMedical Research

Preclinical Safety

Preclinical Secondary Pharmacology

250 Massachusetts Avenue

Cambridge, MA 02139

USA

Jean-Pierre Valentin

UCB Biopharma

Investigative Toxicology, Non-Clinical Development

1420 Braine-l'Alleud

Belgium

Roy J. Vaz

Sanofi US

LGCR – Boston Hub

153 Second Avenue

Waltham, MA 02451

USA

Paul B. Watkins

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

and

The University of North Carolina at Chapel Hill

UNC Eshelman School of Pharmacy

Division of Pharmacotherapy and Experimental Therapeutics

Chapel Hill, NC 27599

USA

Steven Whitebread

Novartis Institutes for BioMedical Research

Preclinical Safety

Preclinical secondary Pharmacology

250 Massachusetts Avenue

Cambridge, MA 02139

USA

Jeffrey L. Woodhead

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Kyunghee Yang

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Yuching Yang

The Hamner Institutes for Health Sciences

The Hamner–UNC Institute for Drug Safety Sciences

Research Triangle Park, NC 27709

USA

Note

1.

Deceased

Preface

In drug discovery, target definition and validation are the first steps, followed by the search for biologically active hits. This can be performed by “wet” screening, optimally by high-throughput techniques, or by virtual screening of large compound libraries or even much larger virtual libraries of chemical structures. Nowadays, one- or two-digit micromolar hits result in most cases and in very short time. After a search for similar compounds that might also be active, medicinal chemists start to optimize their activities against the target under consideration. Nowadays chemists are aware of the problems of “fatty” and large compounds, resulting in poor bioavailability. But a mostly unsolved problem is the optimization with respect to undesired side effects. To understand and tackle these problems, Roy Vaz and Thomas Klabunde edited 7 years ago the book “Antitargets: Prediction and Prevention of Drug Side Effects,” volume 38 of our series “Methods and Principles in Medicinal Chemistry,” in which they discussed the most important targets that might generate undesired or even fatal side effects. Now it is time to discuss some more relevant antitargets and to add recently accumulated knowledge on such targets that were already presented in the earlier volume.

We are very grateful to the editors László Urbán, Vinod F. Patel, and Roy J. Vaz, and all chapter authors for their effort to review all relevant aspects and latest developments in the field of antitarget research. Last but not least, we thank the publisher Wiley-VCH, especially Heike Nöthe, Waltraud Wüst, and Frank Weinreich, for their ongoing support of our series “Methods and Principles in Medicinal Chemistry.”

Düsseldorf Weisenheim am Sand Zürich February 2015

Raimund Mannhold Hugo Kubinyi Gerd Folkers

A Personal Foreword

The concept represented by the book Antitargets [1] was revolutionary when it was published in 2008 with the clear intention to alert the pharmaceutical industry and the medical community to the fact that some therapeutic or unintended off-target activities could translate into serious side effects also known as adverse drug reactions (ADRs). The important message was that one needs to consider all biological effects of a drug or drug candidate, link the adverse drug reactions to molecular targets, and then devise a plan to de-risk these properties in the drug optimization phase. To a great extent, knowledge concerning ADRs has emerged from clinical side effects that were not intended when drugs were initially marketed. One of the first drugs was terfenadine (Seldane) that was withdrawn from use due to sudden deaths caused by torsades de pointes [2]. This drug in the presence of other drugs, such as ketoconazole, prolonged the cardiac QT interval due to unintended modulation of (anti-)targets, including hERG, CYP3A4/5, and P-glycoprotein, among others. The development of in vitro assays for these antitargets rapidly followed, and these assays were introduced into the process of drug discovery. The first book, Antitargets, tried to provide information on the regulatory and human clinical viewpoints, preclinical biology, pharmacology, and medicinal chemistry (structure–activity relationships (SARs)) of these antitargets. In addition, examples were included to demonstrate derisking of these antitarget activities resulting in a cleaner antitarget profile of new clinical candidates. During the writing of the first book, other antitargets emerged and were included, for example, the unexpected cardiac toxicity with 5-HT2B agonism on the use of the anorexigen, fenfluramine.

Black box warnings, failures in drug trials, and drug withdrawals have always been, and continue to be, part of the drug discovery and development and marketed use of drugs. Thus, a new book on antitargets has warranted to continue to capture antitarget information and knowledge not discussed previously and capture broader coverage of related, emerging topics. It is on this basis that sections in this book were assembled. Systems pharmacology, a newer field, has gained prominence and chapters dedicated to the utility in deciphering and modeling antitargets have been included in this book (see Chapters 2 and Chapter 9).

The first section deals with novel technologies and includes description of the utility of adverse event reports to drug discovery, the translational aspects of preclinical safety findings, broader computational prediction of drug side effects, and a description of the serotonergic system – GPCRs, enzymes, and a transporter.

The importance of hepatotoxicity in drug safety warranted several chapters solely on this subject matter. Chapter 5 starts with a view of hepatotoxicity from a clinician's perspective. Chapter 6 includes a review of the most promising predictive biomarkers for hepatotoxicity. A description of the in vitro systems – both assays and their readouts utilized in the early phases of drug discovery – follows in Chapter 7. The role of transporters in the liver, from a pragmatic perspective, provides a deeper understanding of how drugs and their metabolites are distributed throughout the liver. As a case example (http://www.medicinenet.com/bosentan-oral/article.htm), the recent drug labeling of bosentan, resulting from the inhibition of the bile secretion export pump (BSEP) and its consequent drug-induced liver injury (DILI), is described. Finally, description of DILIsym®, an in silico approach combining known mechanisms in a mathematical framework and its application to two drugs, troglitazone and bosentan, is included.

Then follows a collection of chapters on cardiac safety and ion channels, an ever-interesting topic in toxicology. It begins with a review of inotropy and functional safety of the heart followed by updated understandings of three well-known antitarget cardiac ion channels that are important in the action potential generation in a cardiomyocyte, namely, Nav1.5, Cav1.2, and hERG. There is an analysis of a systems pharmacology model and the latest update on hERG channel mechanisms. Also included is a chapter describing common circulating biomarkers for human subjects and preclinical species as a more sensitive method for early safety signals.

The kinase class of antitargets was not discussed in the first book and due to the numerous entries of kinase inhibitors into clinical trials a wealth of human safety data has accumulated on clinical adverse events (AEs) associated [3] with kinase inhibition. This, together with a lack of previous efforts to discuss important side effect profiles of this class of drugs, leads us to dedicate a section to kinase antitargets and their inhibitors. Chapter 15 reviews the known side effects of approved kinase inhibitors, including preclinical and clinical observations. The pharmacological and systems biology approach to understanding and predicting adverse on-mechanism effects is now being systematically applied to each of the targets, which is described in the second chapter. A chapter on cardiotoxicity and protection, specifically related to kinases and their inhibitors, is included. Application of drug discovery tools (structural biology, medicinal chemistry, and in vitro biological assays) to design safer kinase therapeutics is exemplified in the case study.

Some time ago [4], work on the anti-atherosclerotic compound torcetrapib by Pfizer was terminated, due to an increase in blood pressure. This event caused many other research efforts to pause and re-evaluate the development of drugs toward the target, cholesterylester transfer protein (CETP). As in all these types of cases, the question of on-mechanism versus off-mechanism arises. An example of Roche's efforts and how the question was addressed and the outcome are included in this section.

The final chapter of the book is dedicated to those compounds that inadvertently elicit CNS-mediated adverse events and lead to relabeling or withdrawal from the market. A pragmatic description of ways to mitigate these types of safety risks is provided in the last chapter.

Our deep thanks go to our contributing authors for making this book possible through their hard work, dedication, and enthusiasm.

Cambridge, MA Acton, MA Bridgewater, NJ February 2015

László Urbán Vinod F. Patel Roy J. Vaz

References

1.

Vaz, R.J. and Klabunde, R. (eds) (2008)

Antitargets

, Wiley-VCH Verlag GmbH, Weinheim.

2.

Estelle, F. and Simons, R. (1999) H1-receptor antagonists: safety issues.

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3.

Yang, X., Huang, Y., Crowson, M., Li, J., Maitland, M.L., and Lussier, Y.A. (2010) Kinase inhibition-related adverse events predicted from

in vitro

kinome and clinical trial data.

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43

(3), 376–384.

4.

Barter, P.J., Caulfield, M., Erikson, M., Grundy, S.M., Kastelein, J.J.P., Komajda, M., Lopez-Sendon, J., Mosca, L., Tardif, J.C., Waters, D.D., Shear, C.L., Revkin, J.H., Buhr, K.A., Fisher, M.R., Tall, A.R., and Brewer, B. (2007) Effects of torcetrapib in patients at high risk for coronary events.

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Section 1General Concept for Target-based Safety Assessment

1Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance

Steven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán

1.1 Introduction

Drug discovery projects can learn a lot from existing drugs, for instance, how well they perform in a particular indication and patient population, but also which side effects they cause. While efficacies for a particular indication may be quite similar between compounds, their side effect profiles may vary considerably. Many diseases are managed by drugs acting at various targets and diverse chemical structures might be available for the same target. Incidence of adverse drug reactions (ADRs) could vary for drugs acting at the same target due to different off-target profiles and different levels of required exposure of parent and metabolites. These are strongly dependent on the pharmacological interaction with the target (e.g., potency and binding kinetics [1]) and availability in different organs (e.g., blood–brain barrier penetration and high concentrations in the gastrointestinal system or liver).