Antitargets Prediction and Prevention of Drug Side Effects

by Vaz, Roy J.; Klabunde, Thomas; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

• ISBN13: 9783527318216
• ISBN10: 3527318216
• Edition: 1st
• Format: Hardcover
• Copyright: 2008-03-03
• Publisher: Wiley-VCH

Summary

This practice-oriented handbook surveys current knowledge on the prediction and prevention of adverse drug reactions related to off-target activity of small molecule drugs. It is unique in collating the current approaches into a single source, and includes several highly instructive case studies that may be used as guidelines on how to improve drug development projects. With its large section on ADME-related effects, this is key knowledge for every drug developer.

Author Biography

Roy Vaz is the head of investigative pharmacokinetics at the Bridgewater, NJ (USA) location of Sanofi-Aventis Pharmaceuticals. He received his Ph.D. in Organic Chemistry from the University of Florida, Gainesville (USA), after graduating from the Indian Institute of Technology in Mumbai (India). Prior to his present appointment, he has worked with Bristol-Myers-Squibb and Tripos. He is a specialist on the prediction and modeling of cytochrome-mediated drug metabolism.

Thomas Klabunde obtained his PhD in chemistry from the University of M? (Germany). After a postdoctoral fellowship at the Texas A&M University, he was appointed Assistant Professor at the Institute for Bioscience and Technology in Houston (USA). Later on, he joined the pharmaceutical research of Sanofi-Aventis in Frankfurt (Germany), where he is currently a group leader. His main interest lies with drug design approaches for G protein-coupled receptors, notably in the areas of lead finding and chemogenomics.

Table of Contents

List of Contributors

Preface

A Personal Foreword

General Aspects

Why Drugs Fail - A Study on Side Effects in New Chemical Entities

Introduction

Drugs Withdrawn from the Market between 1992 and 2006 Listed Alphabetically

Borderline Cases

Investigational Drugs That Failed in Clinical Phases from 1992 to 2002

Strategies for Avoiding Failure

An Unusual Case: The Revival of Thalidomide

References

Use of Broad Biological Profiling as a Relevant Descriptor to Describe and Differentiate Compounds: Structure-In Vitro (Pharmacology-ADME)-In Vivo (Safety) Relationships

Introduction

Structure-In Vitro Relationships

Chemogenomic Analysis - Target-Target Relationships

In Vitro-In Vivo Relationships - Placing Drug Candidates in the Context of BioPrint

A Perspective for the Future

References

Antitargets: Ion Channels and GPCRs

Pharmacological and Regulatory Aspects of QT Prolongation

Introduction

hERG: Target Versus Antitarget

Pharmacology of QT Prolongation

Significance of Drug-Induced QT Prolongation

Regulatory Aspects of QT Prolongation

Conclusions

References

Introduction

hERG Channel Structure

hERG Potassium Channels and the Cardiac Action Potential

Mutations in hERG Are Associated with Cardiac Arrhythmias

Acquired Long QT Syndrome

Drug-Binding Site of hERG

Structural Basis for hERG Block

Alternative Mechanisms of Block

Role of Inactivation in hERG Block

Inhibition of hERG Trafficking by Pharmacological Agents

Computational Approaches to Predict hERG K? Channel Block

Conclusions

References

QSAR and Pharmacophores for Drugs Involved in hERG Blockage

Introduction

Ligand-Based Models for hERG-Blocking Activity

Ligand-Derived Models in the Light of the hERG Channel Structure

Conclusions

References

GPCR Antitarget Modeling: Pharmacophore Models to Avoid GPCR-Mediated Side Effects

Introduction: GPCRs as Antitargets

In Silico Tools for GPCR Antitarget Modeling

GPCR Antitarget Pharmacophore Modeling: The a1a Adrenergic Receptor

Summary

References

The Emergence of Serotonin 5-HT2B Receptors as DRUG Antitargets

Receptorome Screening to Identify Drug Targets and Antitargets

Post-Receptorome Screening Data Implicate 5-HT2B Receptors in Drug-Induced VHD and PH

Drug Structural Classes and VHD/PH

Conclusions

References

Table of Contents provided by Publisher. All Rights Reserved.