Successful Drug Discovery, Volume 1 E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 409

Veröffentlichungsjahr: 2015

Beschreibung

The first volume of the book series "Successful Drug Discovery" is focusing on new drug discoveries during the last decade, from established drugs to recently introduced drugs of all kinds: small-molecule-, peptide-, and protein-based drugs.
The role of serendipity is analyzed in some very successful drugs where the research targets of the lead molecule and the drug are different. Phenotypic and target-based drug discovery approaches are discussed from the viewpoint of pioneer drugs and analogues.
This volume gives an excellent overview of insulin analogues including a discussion of the properties of rapid-acting and long-acting formulations of this important hormone.
The major part of the book is devoted to case histories of new drug discoveries described by their key inventors. Eight case histories range across many therapeutic fields.
The goal of this book series is to help the participants of the drug research community with a reference book series and to support teaching in medicinal chemistry with case histories and review articles of new drugs.

Leseprobe

Table of Contents

Cover

Related Titles

Title Page

Copyright

Advisory Board Members

Preface

Part I: General Aspects

Chapter 1: Serendipitous Target-Based Drug Discoveries

1.1 Introduction

1.2 Recent Examples of Target-Based Drug Discovery

1.3 Serendipitous Target-Based Drug Discoveries

1.4 Drospirenone (Contraceptive with Anti-aldosterone Activity)

1.5 Escitalopram (Selective Serotonin Reuptake Inhibitor Antidepressant)

1.6 Ezetimibe (Inhibitor of Cholesterol Absorption)

1.7 Lamotrigine (Discovery of a Standalone Drug for the Treatment of Epilepsy)

1.8 Omeprazole (Proton Pump Inhibitor Acid-Suppressive Agent)

1.9 Outlook

Acknowledgments

List of Abbreviations

References

Chapter 2: Drug Discoveries and Molecular Mechanism of Action

2.1 Introduction

2.2 Mechanistic Paradox

2.3 Molecular Mechanism of Action

2.4 How MMOAs were Discovered

2.5 Case Study: Artemisinin

2.6 Summary

List of Abbreviations

References

Part II: Drug Class

Chapter 3: Insulin Analogs – Improving the Therapy of Diabetes

3.1 Introduction

3.2 Pharmacology and Insulin Analogs

3.3 Chemical Description

3.4 Rapid-Acting Insulin Analogs (Prandial or Bolus Insulin)

3.5 Long-Acting Insulin Analog Formulations (Basal Insulin)

3.6 Conclusions and Future Considerations

List of Abbreviations

References

Part III: Case Histories

Chapter 4: The Discovery of Stendra™ (Avanafil) for the Treatment of Erectile Dysfunction

4.1 Introduction

4.2 Discovery of Avanafil

4.3 Pharmacological Features of Avanafil

4.4 Clinical Studies of Avanafil

4.5 Conclusion

List of Abbreviations

References

Chapter 5: Dapagliflozin, A Selective SGLT2 Inhibitor for Treatment of Diabetes

5.1 Introduction

5.2 Role of SGLT2 Transporters in Renal Function

5.3 O-Glucoside SGLT2 Inhibitors

5.4

m

-Diarylmethane C-Glucosides

5.5 Profiling Studies with Dapagliflozin

5.6 Clinical Studies with Dapagliflozin

5.7 Summary

List of Abbreviations

References

Chapter 6: Elvitegravir, A New HIV-1 Integrase Inhibitor for Antiretroviral Therapy

6.1 Introduction

6.2 Discovery of Elvitegravir

6.3 Conclusion

List of Abbreviations

References

Chapter 7: Discovery of Linagliptin for the Treatment of Type 2 Diabetes Mellitus

7.1 Introduction

7.2 Discovery of Linagliptin – High Throughput Screening Hit Optimization

7.3 Rationalization of DPP-4 Inhibition Potency by Crystal Structure Analysis and Studies of Binding Kinetics

7.4 Basic Physicochemical, Pharmacological, and Kinetic Characteristics

7.5 Preclinical Studies

7.6 Clinical Studies

7.7 Conclusion

List of Abbreviations

References

Chapter 8: The Discovery of Alimta (Pemetrexed)

List of Abbreviations

References

Chapter 9: Perampanel: A Novel, Noncompetitive AMPA Receptor Antagonist for the Treatment of Epilepsy

9.1 Introduction

9.2 Seeds Identification by High Throughput Screening (HTS) Assays

9.3 Structure and Activity Relationship (SAR) Study Starting from the Unique Structure of Seed Compounds

9.4 Pharmacological Properties of Perampanel; Selection for Clinical Development

9.5 Clinical Development of Perampanel

9.6 Conclusion

List of Abbreviations

References

Chapter 10: Discovery and Development of Telaprevir (Incivek™) – A Protease Inhibitor to Treat Hepatitis C Infection

10.1 Introduction

10.2 Discussion

10.3 Summary

List of Abbreviations

References

Chapter 11: Antibody–Drug Conjugates: Design and Development of Trastuzumab Emtansine (T-DM1)

11.1 Introduction

11.2 Molecular Design of T-DM1

11.3 Strategies for Bioanalysis

11.4 Strategies for Chemistry and Manufacturing Control

11.5 Nonclinical Development

11.6 Clinical Pharmacology

11.7 Clinical Trials and Approval

11.8 Summary

List of Abbreviations

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Part I: General Aspects

Begin Reading

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 1.4

Figure 1.5

Figure 1.6

Figure 1.7

Figure 1.8

Figure 1.9

Figure 1.10

Figure 1.11

Figure 1.12

Figure 1.13

Figure 1.14

Figure 1.15

Figure 1.16

Figure 1.17

Figure 1.18

Figure 1.19

Figure 1.20

Figure 1.21

Figure 1.22

Figure 1.23

Figure 1.24

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 3.7

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Figure 3.9

Figure 3.10

Figure 3.11

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Scheme 4.1

Scheme 4.2

Figure 4.8

Figure 4.9

Figure 4.10

Figure 4.11

Figure 4.12

Figure 5.1

Figure 5.2

Scheme 5.1

Figure 5.3

Scheme 5.2

Figure 5.4

Figure 5.5

Figure 5.6

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 7.1

Scheme 7.1

Figure 7.2

Scheme 7.2

Figure 7.3

Figure 7.4

Figure 7.5

Figure 7.6

Scheme 8.1

Scheme 8.2

Scheme 8.3

Scheme 8.4

Scheme 8.5

Scheme 8.6

Scheme 8.7

Scheme 8.8

Scheme 8.9

Scheme 8.10

Scheme 8.11

Scheme 8.12

Scheme 8.13

Scheme 8.14

Figure 9.1

Figure 9.2

Figure 9.3

Figure 9.4

Figure 9.5

Figure 9.6

Figure 9.7

Figure 10.1

Figure 10.2

Figure 10.3

Scheme 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 11.1

Figure 11.2

List of Tables

Table 4.1

Table 4.3

Table 4.4

Table 4.2

Table 4.5

Table 4.6

Table 4.7

Table 4.8

Table 5.1

Table 5.2

Table 5.3

Table 5.4

Table 5.5

Table 5.6

Table 5.7

Table 5.8

Table 7.1

Table 7.2

Table 7.3

Table 7.4

Table 9.1

Related Titles

Li, J., Corey, E.J. (eds.)

Drug Discovery

Practices, Processes, and Perspectives

2013

Print ISBN: 978-0-470-94235-2, also available in digital formats

Huang, X., Aslanian, R.G. (eds.)

Case Studies in Modern Drug Discovery and Development

2012

Print ISBN: 978-0-470-60181-5, also available in digital formats

Fischer, J., Ganellin, C.R., Rotella, D.P. (eds.)

Analogue-based Drug Discovery III

2012

Print ISBN: 978-3-527-33073-7, also available in digital formats

Ravina, E.

The Evolution of Drug Discovery

From Traditional Medicines to Modern Drugs

2011

Print ISBN: 978-3-527-32669-3

Fischer, J., Ganellin, C.R. (eds.)

Analogue-based Drug Discovery II

2010

Print ISBN: 978-3-527-32549-8, also available in digital formats

Edited by János Fischer and David P. Rotella

Successful Drug Discovery

The Editors

János Fischer

Gedeon Richter Plc.

Department of Medicinal Chemistry

Gyömröi ut 30

1103 Budapest

Hungary

David P. Rotella

Montclair State University

Department of Chemistry & Biochemistry

1, Normal Ave, Montclair

New Jersey 07043

United States

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.

© 2015 Wiley-VCH Verlag GmbH & 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.

Print ISBN: 978-3-527-33685-2

ePDF ISBN: 978-3-527-67844-0

ePub ISBN: 978-3-527-67845-7

Mobi ISBN: 978-3-527-67846-4

oBook ISBN: 978-3-527-67843-3

Cover Design Susanne Pauker, Singapore

Printing and Binding Markono Print Media Pte Ltd., Singapore

Advisory Board Members

Klaus P. Bøgesø

(Lundbeck, Denmark)

Kazumi Kondo

(Otsuka, Japan)

John A. Lowe III

(JL3Pharma LLC)

Barry V.L. Potter

(University of Bath, UK)

Preface

The International Union of Pure and Applied Chemistry (IUPAC) has supported this new book project; the book has key inventors describe their new drug discoveries and aims to study the general aspects of successful drug discoveries and the optimization in a drug class.

The book Successful Drug Discovery is a continuation of the three volumes of Analogue-based Drug Discovery where analogs of existing drugs were the focus. The new book has a broader scope because it includes both pioneer drugs and their analogs and spans all the important types of small-molecule-, peptide-, and protein-based drugs.

The editors thank the advisory board members: Klaus P. Bøgesø (Lundbeck, Denmark), Kazumi Kondo (Otsuka, Japan), John A. Lowe III (JL3Pharma LLC, USA), and Barry VL Potter (University of Bath, UK). Special thanks are due to the following reviewers who helped both the authors and the editors: Klaus Bøgesø, Derek Buckle, Matthias Eckhardt, Arun Ganesan, William Greenlee, Katalin Hornok, Roy Jefferis, Béla Kiss, Patrizio Mattei, Eckhard Ottow, John Proudfoot, Joerg Senn-Bilfinger, István Tarnawa.

The first volume of Successful Drug Discovery consists of three parts.

Part I: (General Aspects)

Serendipity is an important part of drug discovery that can be present at each step. The first chapter – written by the editors of this book – reveals special serendipitous cases of some important drug discoveries where the key lead molecule and the drug have been discovered on different targets.

David C. Swinney analyzed the molecular mechanism of action in drug discovery. Phenotypic and target-based drug discovery approaches are discussed from the viewpoint of pioneer drugs and analogs.

Part II: (Drug Class)

John M. Beals gives an overview of insulin analogs, which optimize PK/PD profiles but also provide sufficient stability for the treatment of type 1 and type 2 diabetes mellitus. Rapid-acting and long-acting analogs are summarized.

Part III: (Case Histories)

Avanafil

Kiichiro Yamada, Tosiaki Sakamoto, Kenji Omori, and Kohei Kikkawa described the discovery of the new and highly selective PDE5 inhibitor with rapid onset of action. The researchers succeeded in a remarkably short period to create a structurally new drug.

Dapagliflozin

William N. Washburn reports on the discovery of dapagliflozin which was the first SGLT2 inhibitor approved for the treatment of type 2 of diabetes. A C-glucoside side product that was characterized during early SAR studies serendipitiously became the lead structure that ultimately produced the drug.

Elvitegravir

Hisashi Shinkai described the discovery of elvitegravir, a new HIV-1 integrase inhibitor by using a 4-quinolone-3-carboxylic acid scaffold. The once-daily single tablet of a combination of elvitegravir with a CYP3A4 inhibitor and a nucleoside reverse transcriptase inhibitor afforded potent and durable antiretroviral efficacy.

Linagliptin

Matthias Eckhardt, Thomas Klein, Herbert Nar, and Sandra Thiemann have written about the discovery of linagliptin a highly potent and long-acting DPP-4 inhibitor. Linagliptin has a non-linear pharmacokinetic and nonrenal elimination profile, unique within the class of approved DPP-4 inhibitors.

Pemetrexed

Edward C. Taylor gives an overview on the discovery of pemetrexed representing an excellent long term collaboration between academia and industry. The individual interest of the author in pterine chemistry provided a starting point for the discovery of pemetrexed, which is used for the treatment of pleural mesothelioma and non-small cell lung cancer.

Perampanel

Shigeki Hibi described the discovery of perampanel, a novel, noncompetitive AMPA receptor antagonist for the treatment of epilepsy. Starting from HTS, optimization of a promising triaryl-1H-pyridin-2-one scaffold afforded perampanel, which is the first AMPA antagonist approved as an antiepileptic drug.

Telaprevir

B. Govinda Rao, Mark A. Murcko, Mark J. Tebbe, and Ann D. Kwong have written the chapter on the discovery of telaprevir, a protease inhibitor to treat hepatitis C infection. Telaprevir, a NS3/NS4A serine protease inhibitor, was successfully used between 2011 and 2013 in triple combination with ribavirin and interferon.

Trastuzumab emtansine

Sandhya Girish, Gail D. Lewis Phillips, Fredric S. Jacobson, Jagath R. Junutula, and Ellie Guardino described the discovery and development of trastuzumab emtansine. The antibody drug conjugate represents a novel approach in treating patients with HER-2-positive cancer. The drug conjugate enables selective delivery of DM-1, a potent cytotoxic agent, into HER-2-positive target cells.

Last but not least the editors and authors thank the coworkers of Wiley-VCH, especially Dr. Frank Weinreich for the excellent cooperation.

June 2014

Budapest, Hungary

Montclair, NJ, USA

János FischerDavid P. Rotella

Part IGeneral Aspects

Chapter 1Serendipitous Target-Based Drug Discoveries

János Fischer and David P. Rotella

1.1 Introduction

Breakthrough drug discoveries – based on a molecular biological target – can significantly improve therapy for disease. For example, captopril (discovered in 1976) is a pioneer angiotensin-converting enzyme (ACE)-inhibitor used for treatment of essential hypertension. Subsequent compounds acting on the same target (e.g., enalapril, lisinopril, and perindopril) are used for the same purpose. An alternative and complementary treatment for hypertension involves use of angiotension II receptor antagonists. Losartan (discovered in 1986) was the first compound in this class and was followed by several additional molecules (e.g., valsartan, telmisartan, and irbesartan). Treatment of hypertension by these mechanisms provided physicians with additional options to consider as a part of combination therapy or when other possibilities such as diuretics and/or β-blockers are unsatisfactory. For the treatment of obstructive airway diseases several short and long-acting β-2-adrenoreceptor agonists (e.g., salbutamol, formoterol, and salmeterol) that act directly on lung tissue to improve airway function have been discovered. Antimuscarinics selective for M1 and M3 receptors such as tiotropium bromide (discovered in 1989) were found to be effective for treatment of chronic obstructive pulmonary disease (COPD). These distinct mechanisms of action can be used in combination to treat COPD and other complex airway disorders. Imatinib (discovered in 1992) is a BCR-Abl tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia (CML) that demonstrated the concept of targeted chemotherapy substantially improving survival in this difficult to treat disease. In the field of metabolic diseases, sitagliptin (discovered in 2001) was the first dipeptidyl peptidase-IV (DPP-IV) inhibitor for the treatment of type 2 diabetes. The recognition that inhibition of this enzyme could prolong the serum half life of glucagon-like peptide-1 (GLP-1), a peptide hormone that helps tightly regulate blood sugar without substantial risk of hypoglycemia, provided physicians, and patients with another effective mechanistic option for treatment of type 2 diabetes.