Prodrugs and Targeted Delivery E-Book

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

Seitenzahl: 903

Veröffentlichungsjahr: 2010

Beschreibung

This topical reference and handbook addresses the chemistry, pharmacology, toxicology and the patentability of prodrugs, perfectly mirroring the integrated approach prevalent in today's drug design. It summarizes current experiences and strategies for the rational design of prodrugs, beginning at the early stages of the development process, as well as discussing organ- and site-selective prodrugs. Every company employing medicinal chemists will be interested in this practice-oriented overview of a key strategy in modern drug discovery and development.

Leseprobe

Contents

Cover

Methods and Principles in Medicinal Chemistry

Title Page

Copyright

List of Contributors

Preface

A Personal Foreword

Part One: Prodrug Design and Intellectual Property

Chapter 1: Prodrug Strategies in Drug Design

1.1 Prodrug Concept

1.2 Basics of Prodrug Design

1.3 Rationale for Prodrug Design

1.4 History of Prodrug Design

1.5 Recently Marketed Prodrugs

1.6 Concluding Remarks

References

Chapter 2: The Molecular Design of Prodrugs by Functional Group

2.1 Introduction

2.2 The Prodrug Concept and Basics of Design

2.3 Common Functional Group Approaches in Prodrug Design

2.4 Conclusions

References

Chapter 3: Intellectual Property Primer on Pharmaceutical Patents with a Special Emphasis on Prodrugs and Metabolites

3.1 Introduction

3.2 Patents and FDA Approval Process

3.3 Obtaining a Patent

3.4 Conclusion

Part Two: Prodrugs Addressing ADMET Issues

Chapter 4: Increasing Lipophilicity for Oral Drug Delivery

4.1 Introduction

pKa, Degree of Ionization, Partition Coefficient, and Distribution Coefficient

4.3 Prodrug Strategies to Enhance Lipid Solubility

4.4 Prodrug Examples for Antibiotics

4.5 Antiviral Related Prodrugs

4.6 Cardiovascular Related Prodrugs

4.7 Lipophilic Prodrugs of Benzamidine Drugs

4.8 Miscellaneous Examples

4.9 Summary and Conclusion

References

Chapter 5: Modulating Solubility Through Prodrugs for Oral and IV Drug Delivery

5.1 Introduction

5.2 Basics of Solubility and Oral/IV Drug Delivery

5.3 Prodrug Applications for Enhanced Aqueous Solubility

5.4 Challenges with Solubilizing Prodrugs of Insoluble Drugs

5.5 Additional Applications of Prodrugs for Modulating Solubility

5.6 Parallel Exploration of Analogues and Prodrugs in Drug Discovery (Commentary)

5.7 Conclusions

References

Chapter 6: Prodrugs Designed to Target Transporters for Oral Drug Delivery

6.1 Introduction

6.2 Serendipity: An Actively Transported Prodrug

6.3 Requirements for Actively Transported Prodrugs

6.4 Peptide Transporters: PEPT1 and PEPT2

6.5 Monocarboxylate Transporters

6.6 Bile Acid Transporters

6.7 Conclusions

References

Chapter 7: Topical and Transdermal Delivery Using Prodrugs: Mechanism of Enhancement

7.1 Introduction

7.2 Arrangement of Water in the Stratum Corneum

7.3 A New Model for Diffusion Through the Stratum Corneum: The Biphasic Solubility Model

7.4 Equations for Quantifying Effects of Solubility on Diffusion Through the Stratum Corneum

7.5 Design of Prodrugs for Topical and Transdermal Delivery Based on the Biphasic Solubility Model

7.6 Comparison of Human and Mouse Skin Experiments

7.7 Summary

References

Chapter 8: Ocular Delivery Using Prodrugs

8.1 Introduction

8.2 Criteria for an Ideal Ophthalmic Prodrug

8.3 Anatomy and Physiology of the Eye

8.4 Barriers to Ocular Drug Delivery

8.5 Influx and Efflux Transporters on the Eye

8.6 Transporter-Targeted Prodrug Approach

8.7 Drug Disposition in Ocular Delivery

8.8 Effect of Physiochemical Factors on Drug Disposition in Eye

8.9 Prodrug Strategy to Improve Ocular Bioavailability (Nontransporter-Targeted Approach)

8.10 Recent Patents and Marketed Ocular Prodrugs

8.11 Novel Formulation Approaches for Sustained Delivery of Prodrugs

8.12 Conclusion

Acknowledgments

References

Chapter 9: Reducing Presystemic Drug Metabolism

9.1 Introduction

9.2 Presystemic Metabolic Barriers

9.3 Prodrug Approaches to Reduce Presystemic Drug Metabolism

9.4 Targeting Colon

9.5 Targeting Lymphatic Route

9.6 Conclusion

References

Chapter 10: Enzyme-Activated Prodrug Strategies for Site-Selective Drug Delivery

10.1 Introduction

10.2 General Requirements for Enzyme-Activated Targeted Prodrug Strategy

10.3 Examples of Targeted Prodrug Strategies

10.4 Summary

Acknowledgment

References

Chapter 11: Prodrug Approaches for Central Nervous System Delivery

11.1 Blood–Brain Barrier in CNS Drug Development

11.2 Prodrug Strategies

11.3 Prodrug Strategies Based Upon BBB Nutrient Transporters

11.4 Prodrug Strategies Based Upon BBB Receptors

11.5 CNS Prodrug Summary

Acknowledgments

References

Chapter 12: Directed Enzyme Prodrug Therapies

12.1 Introduction

12.2 Theoretical Background of DEPT

12.3 Comparison of ADEPT and GDEPT

12.4 Enzymes in ADEPT and GDEPT

12.5 Design of Prodrugs

12.6 Strategies Used for the Improvement of DEPT Systems

12.7 Biological Data for ADEPT and GDEPT

12.8 Conclusions

Acknowledgments

References

Part Three: Codrugs and Soft Drugs

Chapter 13: Improving the Use of Drug Combinations Through the Codrug Approach

13.1 Codrugs and Codrug Strategy

13.2 Ideal Codrug Characteristics

13.3 Examples of Marketed Codrugs

13.4 Topical Codrug Therapy for the Treatment of Ophthalmic Diseases

13.5 Codrugs for Transdermal Delivery

13.6 Codrugs of L-DOPA for the Treatment of Parkinson's Disease

13.7 Analgesic Codrugs Containing Nonsteroidal Anti-Inflammatory Agents

13.8 Analgesic Codrugs of Opioids and Cannabinoids

13.9 Codrugs Containing Anti-HIV Drugs

References

Chapter 14: Soft Drugs

14.1 Introduction

14.2 Indications

14.3 Design Considerations

14.4 Case Study: The Discovery of Esmolol

14.5 Summary

References

Part Four: Preclinical and Clinical Consideration for Prodrugs

Chapter 15: Pharmacokinetic and Biopharmaceutical Considerations in Prodrug Discovery and Development

15.1 Introduction

15.2 Understanding Pharmacokinetic/Pharmacodynamic Relationships

15.3 Pharmacokinetics

15.4 Tools for the Prodrug Scientist

15.5 Enzymes Involved with Prodrug Conversion

15.6 Use of the Caco-2 System for Permeability and Active Transport Evaluation

15.7 XP13512: Improving PK Performance by Targeting Active Transport

15.8 Prodrug Absorption: Transport/Metabolic Conversion Interplay

15.9 Preabsorptive Degradation

15.10 Biopharmaceutical-Based PK Modeling for Prodrug Design

15.11 Conclusions

References

Chapter 16: The Impact of Pharmacogenetics on the Clinical Outcomes of Prodrugs

16.1 Introduction

16.2 Clopidogrel and CYP2C19

16.3 Codeine and CYP2D6

16.4 Tamoxifen and CYP2D6

16.5 Fluorouracil Prodrugs and Carboxylesterase

16.6 Irinotecan and Carboxylesterase 2

16.7 Others

16.8 Drug Development Implication

16.9 Conclusions

References

Index

Methods and Principles in Medicinal Chemistry

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

Editorial Board

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

Previous Volumes of this Series:

Smit, Martine J. / Lira, Sergio A. / Leurs, Rob (Eds.)

Chemokine Receptors as Drug Targets

2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases as Therapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead Profiling

Identification and Optimization of Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)

Epigenetic Targets in Drug Discovery

2009

ISBN: 978-3-527-32355-5

Vol. 42

Todeschini, Roberto / Consonni, Viviana

Molecular Descriptors for Chemoinformatics

Volume I: Alphabetical Listing /

Volume II: Appendices, References

2009

ISBN: 978-3-527-31852-0

Vol. 41

van de Waterbeemd, Han / Testa, Bernard (Eds.)

Drug Bioavailability

Estimation of Solubility, Permeability, Absorption and Bioavailability

Second, Completely Revised Edition

2008

ISBN: 978-3-527-32051-6

Vol. 40

Ottow, Eckhard/Weinmann, Hilmar (Eds.)

Nuclear Receptors as Drug Targets

2008

ISBN: 978-3-527-31872-8

Vol. 39

Vaz, Roy J. / Klabunde, Thomas (Eds.)

Antitargets

Prediction and Prevention of Drug Side Effects

2008

ISBN: 978-3-527-31821-6

Vol. 38

Mannhold, Raimund (Ed.)

Molecular Drug Properties

Measurement and Prediction

2007

ISBN: 978-3-527-31755-4

Vol. 37

Series Editors

Prof. Dr. Raimund Mannhold

Molecular Drug Research Group

Heinrich-Heine-Universität

Universitätsstrasse 1

40225 Düsseldorf

Germany

[email protected]

Prof. Dr. Hugo Kubinyi

Donnersbergstrasse 9

67256 Weisenheim am Sand

Germany

[email protected]

Prof. Dr. Gerd Folkers

Collegium Helveticum

STW/ETH Zurich

8092 Zurich

Switzerland

[email protected]

Volume Editor

Prof. Dr. Jarkko Rautio

University of Eastern Finland

School of Pharmacy

Yliopistonranta 1

70211 Kuopio

Finland

Cover Description

Prodrugs are bioreversible derivatives of drug molecules that can address ADME issues (“backbone”) and must undergo an enzymatic and/or chemical transformation in vivo to release the pharmacologically active parent drug. A representative prodrug is oseltamivir (Tamiflu®).

(Laskowski anatomy taken with courtesy of the U.S. National Library of Medicine)

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.

© 2011 WILEY-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

ISBN: 978-3-527-32603-7

List of Contributors

Jane P.F. Bai

US Food and Drug Administration

Center for Drug Evaluation and Research

Office of Translational Science

Office of Clinical Pharmacology

10903 New Hampshire, Ave.

Silver Spring

MD 20993

USA

Eyal H. Barash

Barash Law LLC

3000 Kent Avenue

West Lafayette

IN 47906

USA

Ujjwal Chakraborty

University of Kentucky

Department of Chemistry

Lexington

KY 40536-0082

USA

Peter A. Crooks

University of Kentucky

College of Pharmacy

Department of Pharmaceutical Sciences

Lexington

KY 40536-0082

USA

Harpreet K. Dhooper

University of Kentucky

Department of Chemistry

Lexington

KY 40536-0082

USA

Paul W. Erhardt

The University of Toledo College of Pharmacy

Center for Drug Design and Development

Toledo

OH

USA

Ripal Gaudana

University of Missouri-Kansas City

School of Pharmacy

Division of Pharmaceutical Sciences

Kansas City

MO

USA

Victor R. Guarino

Bristol-Myers Squibb

Pharmaceutical Candidate

Optimization

Princeton

NJ 08543

USA

Douglas Hedley

Institute of Cancer Research

CRC Centre for Cancer Therapeutics

15 Cotswold Road

Sutton

Surrey SM2 5NG

UK

Kristiina Huttunen

University of Eastern Finland

School of Pharmacy

Yliopistonranta 1

FI-70211 Kuopio

Finland

Jwala Jwala

University of Missouri-Kansas City

School of Pharmacy

Division of Pharmaceutical Sciences

Kansas City

MO

USA

Deep Kwatra

University of Missouri-Kansas City

School of Pharmacy

Division of Pharmaceutical Sciences

Kansas City

MO

USA

Krista Laine

University of Eastern Finland

School of Pharmacy

Yliopistonranta 1

FI-70211 Kuopio

Finland

Lawrence L. Lesko

US Food and Drug Administration

Center for Drug Evaluation and Research

Office of Translational Science

Office of Clinical Pharmacology

10903 New Hampshire, Ave.

Silver Spring

MD 20993

USA

Paul R. Lockman

Texas Tech University Health Sciences Center

Department of Pharmaceutical Sciences

1406 Coulter

Amarillo

TX 79106

USA

Susruta Majumdar

Memorial Sloan

Kettering Cancer Center

Laboratory of Chemistry, Pharmacology,

and Neuroscience

1275 York Avenue

New York

NY 10021

USA

Ashim K. Mitra

University of Missouri-Kansas City

School of Pharmacy

Division of Pharmaceutical Sciences

Kansas City

MO

USA

Majid Y. Moridani

Texas Tech University

Health Sciences Center

Amarillo

TX 79106

USA

Gabriel Negoita-Giras

Institute of Cancer Research

CRC Centre for Cancer Therapeutics

15 Cotswold Road

Sutton

Surrey SM2 5NG

UK

Dan Niculescu-Duvaz

Institute of Cancer Research

CRC Centre for Cancer Therapeutics

15 Cotswold Road

Sutton

Surrey SM2 5NG

UK

John P. O'Donnell

Pfizer Global Research and Development

Department of Antibacterials Research

Eastern Point Road

Groton

CT 06340

USA

Mike Pacanowski

US Food and Drug Administration

Center for Drug Evaluation and Research

Office of Translational Science

Office of Clinical Pharmacology

10903 New Hampshire, Ave.

Silver Spring

MD 20993

USA

Atiqur Rahman

US Food and Drug Administration

Center for Drug Evaluation and Research

Office of Translational Science

Office of Clinical Pharmacology

10903 New Hampshire, Ave.

Silver Spring

MD 20993

USA

Jarkko Rautio

University of Eastern Finland

School of Pharmacy

Yliopistonranta 1

FI-70211 Kuopio

Finland

Michael D. Reese

The University of Toledo College of Pharmacy

Center for Drug Design and Development

Toledo

OH

USA

Kenneth Sloan

University of Florida

Department of Medicinal Chemistry

1600 SW Archer Road P6-20

Gainesville

FL 32610

USA

Quentin R. Smith

Texas Tech University

Health Sciences Center

Department of Pharmaceutical Sciences

1406 Coulter

Amarillo

TX 79106

USA

Caroline J. Springer

Institute of Cancer Research

CRC Centre for Cancer Therapeutics

15 Cotswold Road

Sutton

Surrey SM2 5NG

UK

Ravi Vaishya

University of Missouri-Kansas City

School of Pharmacy

Division of Pharmaceutical Sciences

Kansas City

MO

USA

Scott C. Wasdo

University of Florida

Department of Anesthesiology

1600 SW Archer Road M5-16

Gainesville

FL 32610

USA

Mark S. Warren

XenoPort, Inc.

3410 Central Expressway

Santa Clara

CA 95051

USA

Preface

Historically, biological screening of new compounds was performed in animals. Application by the enteral route automatically provided a first overview on bioavailability and biological half-life. Nowadays, lead structure search and optimization are dominated by in vitro screening systems. Correspondingly, problems in compound liberation, oral absorption, organ distribution, metabolism, and excretion (LADME) are often observed at a relatively late stage. The problems may already result either from inappropriate lead structure selection or from unidirectional affinity optimization, without sufficient consideration for solubility, permeation properties, and metabolic stability. However, there are many options to rescue a preclinical candidate with such problems. Liberation can be enhanced by increasing the solubility via the formation of polar derivatives, for example, phosphates, reduction of carbonyl to hydroxyl groups, or introduction of polar, most often basic residues, where they do not negatively interfere with binding. Absorption can be enhanced by making the compound more lipophilic in first line by the conversion of acids into esters. Distribution can be influenced by using transporters, for example, for the blood–brain barrier penetration of L-DOPA, or by designing compounds that are preferentially metabolized in a certain organ or tumor, for example, omeprazole or capecitabine. Metabolism can be easily controlled by avoiding or introducing metabolically labile groups.

Prodrugs are inactive or less active drug analogues or derivatives that have better physicochemical or pharmacokinetic properties than their parent drugs. They are more or less specifically metabolized to the active form of the drug. There are manifold reasons for the development of a prodrug. In most cases, prodrugs are designed for a drug that is not sufficiently bioavailable. Other reasons are that the drug does not permeate the blood–brain barrier, the drug has poor solubility or taste, the drug has no sufficient chemical stability, or the drug has no sufficient organ or cell specificity. Soft drugs (sometimes also called antedrugs) are drugs with very short half-life or without systemic activity. Some esters of corticosteroid carboxylic acids are topically active; after dermal absorption, they are metabolically degraded to inactive analogues, in this manner avoiding systemic side effects. Targeted drugs are drugs or prodrugs that exert their biological action only in certain organs or cells.

We are very grateful to Jarkko Rautio, who assembled a team of leading experts to discuss all these concepts. In a comprehensive manner, strategies are presented to rescue a drug candidate with insufficient ADME properties. For this purpose, the book is well suited both for all practitioners in medicinal chemistry and for graduate students who want to learn about rational concepts of lead structure optimization. We are also grateful to Frank Weinreich and Nicola Oberbeckmann-Winter for their ongoing support and enthusiasm for our book series, Methods and Principles in Medicinal Chemistry, of which this book is another highlight.

October 2010

Raimund Mannhold, Düsseldorf

Hugo Kubinyi, Weisenheim am Sand

Gerd Folkers, Zurich

A Personal Foreword

The prodrug concept, as first introduced by Adrian Albert in the 1950s, defines a prodrug as a pharmacologically inactive agent that undergoes an enzymatic and/or chemical transformation in vivo to a therapeutically active drug. Prodrug strategies have traditionally been used to address ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties and risks of marketed drugs or as a tool in late-stage problem solving for drug development candidates. However, prodrugs are now increasingly being integrated into early drug discovery. Indeed, the successful application of prodrug strategies over the past two decades has significantly increased the percentage of drugs approved as prodrugs to an eye-catching 10%. In addition, the percentage of prodrugs among the world's top-selling drugs is particularly high, including blockbusters such as all the proton pump inhibitor “prazoles,” the antiplatelet agent clopidogrel, and the hypercholesterolemia drugs simvastatin and fenofibrate, to name a few.

The success of prodrugs can also be seen in the literature. Books, book chapters, and numerous research and review articles have been published in recent years, with the compilation of the prodrug two-volume book in 2007 by AAPS Press/Springer and edited by Professor Valentino Stella et al. certainly providing the most comprehensive overview of early and current prodrug strategies. So why do we need a new book on prodrugs so soon? The idea of this new prodrug book was mulled over by several prodrug enthusiasts, and it soon became obvious that there are topics that are not really addressed in the existing works. Moreover, I think the more perspectives we can explore on strategies suitable for a prodrug approach, or when they should not be pursued, the better off we will be scientifically. Thus, with some trepidation regarding content, especially trying to avoid extensive redundancy, the task was indeed found worth rewarding and invigorating.

This volume of Methods and Principles in Medicinal Chemistry contains various strategies for prodrug design and highlights many examples of prodrugs that either have been launched or are undergoing experimental assessment. Part One begins with a historical overview and is followed by approaches of prodrug design and the concepts of prodrug patentability. Part Two focuses on the ADMET issues that can be addressed by prodrugs, ranging from permeability and solubility to targeting. In Part Three, the emphasis is on codrugs, which consist of two active drugs incorporated into a single chemical entity, and soft drugs, which in contrast to prodrugs are designed to undergo inactivation after their biotransformation. Both prodrugs and soft drugs rely upon biotransformation to dictate their course of activation and are worth discussing in the same context. Part Four is devoted to preclinical and clinical considerations for prodrugs providing a discovery screening strategy for evaluation of prodrugs and pharmacogenetic focus for prodrugs.

I want to express my sincere gratitude to all authors for their excellent efforts and cooperation. It has been a pleasure for me to be involved with all of these high-profile prodrug enthusiasts. I also want to acknowledge the people at Wiley-VCH, namely, Dr Nicola Oberbeckmann-Winter for her tireless support in the production of this book and Dr Hugo Kubinyi for his valuable advice on its content. I truly hope that this book will stimulate multidisciplinary teams of medicinal chemists, biologists, and other scientists in drug design and development process to consider a prodrug approach as a rational tool in drug discovery that will ultimately lead to better drugs.

October 2010

Jarkko Rautio, Kuopio

Part One

Prodrug Design and Intellectual Property