Analogue-based Drug Discovery III E-Book

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

Seitenzahl: 635

Veröffentlichungsjahr: 2012

Beschreibung

Most drugs are analogue drugs. There are no general rules how a new drug can be discovered, nevertheless, there are some observations which help to find a new drug, and also an individual story of a drug discovery can initiate and help new discoveries. Volume III is a continuation of the successful book series with new examples of established and recently introduced drugs. The major part of the book is written by key inventors either as a case study or a study of an analogue class. With its wide range across a variety of therapeutic fields and chemical classes, this is of interest to virtually every researcher in drug discovery and pharmaceutical chemistry, and -- together with the previous volumes -- constitutes the first systematic approach to drug analogue development.

Leseprobe

Contents

Cover

Related Titles

Title Page

Copyright

Preface

Part I (General Aspects)

Part II (Drug Classes)

Part III (Case Histories)

List of Contributors

Part I: General Aspects

Chapter 1: Pioneer and Analogue Drugs

1.1 Monotarget Drugs

1.2 Dual-Acting Drugs

1.3 Multitarget Drugs

1.4 Summary

Acknowledgments

References

Chapter 2: Competition in the Pharmaceutical Drug Development

2.1 Introduction

2.2 Analogue-Based Drugs: Just Copies?

2.3 How Often Does Analogue-Based Activity Occur? Insights from the GPCR Patent Space

References

Chapter 3: Metabolic Stability and Analogue-Based Drug Discovery

List of Abbreviations

3.1 Introduction

3.2 Metabolism-Guided Drug Design

3.3 Indirect Modulation of Metabolism by Fluorine Substitution

3.4 Modulation of Low Clearance/Long Half-Life via Metabolism-Guided Design

3.5 Tactics to Resolve Metabolism Liabilities Due to Non-CYP Enzymes

3.6 Eliminating RM Liabilities in Drug Design

3.7 Eliminating Metabolism-Dependent Mutagenicity

3.8 Eliminating Mechanism-Based Inactivation of CYP Enzymes

3.9 Identification (and Elimination) of Electrophilic Lead Chemical Matter

3.10 Mitigating Risks of Idiosyncratic Toxicity via Elimination of RM Formation

3.11 Case Studies on Elimination of RM Liability in Drug Discovery

3.12 Concluding Remarks

References

Chapter 4: Use of Macrocycles in Drug Design Exemplified with Ulimorelin, a Potential Ghrelin Agonist for Gastrointestinal Motility Disorders

4.1 Introduction

4.2 High-Throughput Screening Results and Hit Selection

4.3 Macrocycle Structure–Activity Relationships

4.4 PK–ADME Considerations

4.5 Structural Studies

4.6 Preclinical Evaluation

4.7 Clinical Results and Current Status

4.8 Summary

References

Part II: Drug Classes

Chapter 5: The Discovery of Anticancer Drugs Targeting Epigenetic Enzymes

List of Abbreviations

5.1 Epigenetics

5.2 DNA Methyltransferases

5.3 5-Azacytidine (Azacitidine, Vidaza) and 5-Aza-2′-deoxycytidine (Decitabine, Dacogen)

5.4 Other Nucleoside DNMT Inhibitors

5.5 Preclinical DNMT Inhibitors

5.6 Zinc-Dependent Histone Deacetylases

5.7 Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat, Zolinza)

5.8 FK228 (Depsipeptide, Romidepsin, Istodax)

5.9 Carboxylic Acid and Benzamide HDAC Inhibitors

5.10 Prospects for HDAC Inhibitors

5.11 Epigenetic Drugs – A Slow Start but a Bright Future

Acknowledgments

References

Chapter 6: Thienopyridyl and Direct-Acting P2Y12 Receptor Antagonist Antiplatelet Drugs

List of Abbreviations

6.1 Introduction

6.2 Thienopyridines

6.3 Direct-Acting P2Y12 Antagonists

6.4 Summary

References

Chapter 7: Selective Estrogen Receptor Modulators

List of Abbreviations

7.1 Introduction

7.2 Tamoxifen

7.3 Raloxifene

7.4 Summary

References

Chapter 8: Discovery of Nonpeptide Vasopressin V2 Receptor Antagonists

List of Abbreviations

8.1 Introduction

8.2 Peptide AVP Agonists and Antagonists

8.3 Lead Generation Strategies [20, 21]

8.4 Lead Generation Strategy-2, V2 Receptor Affinity [28]

8.5 Lead Optimization [33]

8.6 Reported Nonpeptide Vasopressin V2 Receptor Antagonist Compounds

8.7 Conclusions

References

Chapter 9: The Development of Cysteinyl Leukotriene Receptor Antagonists

List of Abbreviations

9.1 Introduction

9.2 Scope of the Drug Discovery Effort on Leukotriene Modulators

9.3 Synthetic Leukotriene Production and Benefits Derived from this Effort

9.4 Bioassays and General Drug Discovery Testing Cascade

9.5 Development of Antagonists – General Approaches

9.6 Discovery of Zafirlukast

9.7 Discovery of Montelukast

9.8 Discovery of Pranlukast

9.9 Comparative Analysis and Crossover Impact

9.10 Postmarketing Issues

9.11 Conclusions

9.12 Acknowledgment

9.13 Disclaimer

References

Part III: Case Studies

Chapter 10: The Discovery of Dabigatran Etexilate

List of Abbreviations

10.1 Introduction

10.2 Dabigatran Design Story

10.3 Preclinical Pharmacology Molecular Mechanism of Action of Dabigatran

10.4 Clinical Studies and Indications

10.5 Summary

References

Chapter 11: The Discovery of Citalopram and Its Refinement to Escitalopram

List of Abbreviations

11.1 Introduction

11.2 Discovery of Talopram

11.3 Discovery of Citalopram

11.4 Synthesis and Production of Citalopram

11.5 The Pharmacological Profile of Citalopram

11.6 Clinical Efficacy of Citalopram

11.7 Synthesis and Production of Escitalopram

11.8 The Pharmacological Profile of the Citalopram Enantiomers

11.9 R-Citalopram's Surprising Inhibition of Escitalopram

11.10 Binding Site(s) for Escitalopram on the Serotonin Transporter

11.11 Future Perspectives on the Molecular Basis for Escitalopram's Interaction with the SERT

11.12 Clinical Efficacy of Escitalopram

11.13 Conclusions

References

Chapter 12: Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol

List of Abbreviations

12.1 Introduction

12.2 The Discovery of Tapentadol

12.3 The Preclinical and Clinical Profile of Tapentadol

12.4 Summary

References

Chapter 13: Novel Taxanes: Cabazitaxel Case Study

List of Abbreviations

13.1 Introduction

13.2 Cabazitaxel Structure–Activity Relationships and Chemical Synthesis

13.3 Cabazitaxel Preclinical and Clinical Development

13.4 Summary

Acknowledgments

References

Chapter 14: Discovery of Boceprevir and Narlaprevir: A Case Study for Role of Structure-Based Drug Design

List of Abbreviations

References

Chapter 15: A New-Generation Uric Acid Production Inhibitor: Febuxostat

List of Abbreviations

15.1 Introduction

15.2 Xanthine Oxidoreductase – Target Protein for Gout Treatment

15.3 Mechanism of XOR Inhibition by Allopurinol

15.4 Development of Nonpurine Analogue Inhibitor of XOR: Febuxostat

15.5 Mechanism of XOR Inhibition by Febuxostat

15.6 Excretion of XOR Inhibitors

15.7 Results of Clinical Trials of Febuxostat in Patients with Hyperuricemia and Gout

15.8 Summary

15.9 Added in Proof

References

Index

Related Titles

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

Analogue-based Drug Discovery II

2010

ISBN: 978-3-527-32549-8

IUPAC, Fischer, J., Ganellin, C. R. (Eds.)

Analogue-based Drug Discovery

2006

ISBN: 978-3-527-31257-3

Abraham, D. J., Rotella, D. P.

Burger's Medicinal Chemistry, Drug Discovery and Development

8 Volume Set

2010

ISBN: 978-0-470-27815-4

Li, J. J., Johnson, D. S. (eds.)

Modern Drug Synthesis

2010

ISBN: 978-0-470-52583-8

Lednicer, D.

Strategies for Organic Drug Synthesis and Design

2008

ISBN: 978-0-470-19039-5

Chorghade, M. S. (ed.)

Drug Discovery and Development

2 Volume Set

2007

ISBN: 978-0-471-39846-2

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Preface

The editors of the third volume of the book series “Analogue-Based Drug Discovery” thank the International Union of Pure and Applied Chemistry (IUPAC) for supporting this book project. We also thank the coworkers at Wiley-VCH, Dr. Frank Weinreich and Waltraud Wüst, for their excellent help, and last but not least we are grateful to all the contributors of this book. Special thanks are due to the following reviewers who helped both the authors and the editors: Klaus Peter Bøgesø, Helmut Buschmann, Paul W. Erhardt, Staffan Erickson, Susan B. Horwitz, Manfred Jung, Amit Kalgutkar, Danijel Kikelj, Andrew MacMillan, Eckhard Ottow, Jens-Uwe Peters, Henning Priepke, John Proudfoot, Stephen C. Smith, Bernard Testa, and Han van de Waterbeemd.

Analogue-based drug discovery is a basic principle of drug research. In this book series, we focused on analogues of existing drugs. In the first volume (2006), we discussed structural and pharmacological analogues, whereas the second volume (2010) also included analogues with pharmacological similarities.

In this volume, we continued the same concept, recognizing that in several cases there is only a narrow gap between a pioneer and an analogue drug because of the strong competitive environment in the industry. A new promising molecular biological target inspires parallel research efforts at several companies. It can happen that the first discovery does not lead to a marketed drug; instead, a molecule discovered later proves to be the first to be launched. As a result of the strong competition, it can also happen that two pioneer drugs are introduced nearly simultaneously in the market, and these drugs often have chemical and pharmacological similarities.

The third volume of Analogue-Based Drug Discovery consists of three parts.

Part I (General Aspects)

The introductory chapter discusses the relationship between the pioneer and analogue drugs, where their overlapping character can be observed. A chapter by Christian Tyrchan and Fabrizio Giordanetto (AstraZeneca) analyzes competition in pharmaceutical drug development. Amit S. Kalgutkar and Antonia F. Stepan (Pfizer) study the important role of metabolic stability in drug research. Mark L. Peterson, Hamit Hoveyda, Graeme Fraser, Éric Marsault, and René Gagnon (Tranzyme Pharma Inc.) write on the use of peptide-based macrocycles in drug design exemplified with the discovery of ulimorelin.

Part II (Drug Classes)

A. Ganesan (University of East Anglia) gives an overview of discovery research into anticancer epigenetic drugs. Joseph A. Jakubowski (Lilly) and Atsushiro Sugidachi (Daiichi Sankyo) evaluate the structurally diverse drug class of the antithrombotic P2Y12 receptor antagonists. Paul Erhardt, Amarjit Luniwal, and Rachael Jetson (University of Toledo, USA) summarize the medicinal chemistry of selective estrogen receptor modulators. Kazumi Kondo and Hidenori Ogawa (Otsuka Phramaceutical Co., Japan) describe the discovery of aquaretics that are vasopressin V2 receptor antagonists. Peter R. Bernstein (PhaRmaB LLC) evokes the discovery of cysteinyl leukotriene receptor antagonists that are important in the treatment of asthma.

Part III (Case Histories)

Norbert Hauel, Andreas Clemens, Herbert Nar, Henning Priepke, Joanne van Ryn, and Wolfgang Wienen (Boehringer Ingelheim, Biberach, Germany) report on the discovery of dabigatran etexilate, an oral direct thrombin inhibitor approved for use in the treatment of acute thrombosis. Klaus P. Bøgesø and Connie Sánchez (Lundbeck) describe the discovery of escitalopram, which is one of the most successful selective serotonin reuptake inhibitors in the treatment of depressive disorders. Helmut Buschmann (Pharma-Consulting, Aachen, Germany) analyzes the discovery of tapentadol, a novel centrally acting synthetic analgesic with a dual mechanism of action. Hervé Bouchard, Drothée Semiond, Marie-Laure Risse, and Patricia Vrignaud (Sanofi) describe the discovery of cabazitaxel, a novel semisynthetic taxane, a new anticancer drug. Srikanth Venkatraman, Andrew Prongay, and George F. Njoroge (Merck) summarize the discovery of boceprevir and narlaprevir, hepatitis C protease inhibitors. Ken Okamoto, Shiro Kondo, and Takeshi Nishino (Nippon Medical School, Teijin Ltd, and University of Tokyo) describe the discovery of febuxostat, a new uric acid production inhibitor.

The above 15 chapters of the book with 40 authors from 9 countries bring important and successful drug discoveries closer to the medicinal chemists and to all who are interested in the complicated history of drug discoveries.

The major parts of the chapters are written by key inventors.

We hope that also the third volume of this book series will be well received by people interested in medicinal chemistry.

May 2012

Budapest, Hungary

London, UK

Montclair, NJ, USA

János FischerC. Robin GanellinDavid P. Rotella

List of Contributors

Peter R. Bernstein

PhaRmaB LLC

14 Forest View Road

Rose Valley, PA 1908-6721

USA

Klaus P. Bøgesø

H. Lundbeck A/S

Lundbeck Research Denmark

9 Ottiliavej

2500 Valby

Denmark

Hervé Bouchard

Sanofi

LGCR/Natural Product & Protein Chemistry (NPPC)

13 quai Jules Guesde

94400 Vitry-sur-Seine

France

Helmut Buschmann

Sperberweg 15

52076 Aachen

Germany

Andreas Clemens

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Paul Erhardt

The University of Toledo

College of Pharmacy

2801 West Bancroft Street

Toledo, OH 43606-3390

USA

János Fischer

Gedeon Richter Plc.

Department of Medicinal Chemistry

Gyömröi ut 19/21

1103 Budapest

Hungary

Graeme Fraser

Tranzyme Pharma, Inc.

3001, 12th Avenue Nord

Sherbrooke, Quebec J1H 5N4

Canada

René Gagnon

Tranzyme Pharma, Inc.

3001, 12th Avenue Nord

Sherbrooke, Quebec J1H 5N4

Canada

C. Robin Ganellin

University College London

Department of Chemistry

20 Gordon Street

London WC1H 0AJ

UK

A. Ganesan

School of Pharmacy

University of East Anglia

Norwich NR4 7TJ

United Kingdom

Fabrizio Giordanetto

AstraZeneca CV/GI

Lead Generation Department

Pepparedsleden 1

43150 Mölndal

Sweden

Norbert Hauel

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Hamid Hoveyda

Tranzyme Pharma, Inc.

3001, 12th Avenue Nord

Sherbrooke, Quebec J1H 5N4

Canada

Joseph A. Jakubowski

Eli Lilly and Company

Lilly Research Laboratories

Indianapolis, IN 46285

USA

Rachael Jetson

The University of Toledo

College of Pharmacy

2801 West Bancroft Street

Toledo, OH 43606-3390

USA

Amit S. Kalgutkar

Pfizer Worldwide Research and Development

Department of Pharmacokinetics, Dynamics, and Metabolism

MS 8220-3529

Groton CT 06340

USA

Kazumi Kondo

Otsuka Pharmaceutical Co. Ltd.

Qs' Research Institute 463-10 Kagasuno, Kawauchicho

Tokushima 771-0192

Japan

Shiro Kondo

Teijin Ltd.

Kondo Laboratory

4-3-2 Asahigaoka, Hino

Tokyo 191–8512

Japan

Amarjit Luniwal

The University of Toledo

College of Pharmacy

2801 West Bancroft Street

Toledo, OH 43606-3390

USA

Éric Marsault

Tranzyme Pharma, Inc.

3001, 12th Avenue Nord

Sherbrooke, Quebec J1H 5N4

Canada

Herbert Nar

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Takeshi Nishino

The University of Tokyo

Graduate School of Agricultural and Life Sciences

Department of Applied Biological Chemistry

1-1-1 Yayoi, Bunkyo-Ku

Tokyo 113–8657

Japan

George F. Njoroge

Eli Lilly and Company

Lilly Research Laboratories

Indianapolis, IN 46285

USA

Hidenori Ogawa

Otsuka Pharmaceutical Co. Ltd.

Qs' Research Institute

463-10 Kagasuno, Kawauchicho

Tokushima 771-0192

Japan

Ken Okamoto

Nippon Medical School

Department of Biochemistry

1-1-5 Sendagi, Bunkyo-ku

Tokyo 113-8602

Japan

Mark L. Peterson

Tranzyme Pharma, Inc.

3001, 12th Avenue Nord

Sherbrooke, Quebec J1H 5N4

Canada

Henning Priepke

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Andrew Prongay

Merck Research Laboratories Chemical Research

2015 Galloping Hill Road Kenilworth, NJ 07033

USA

Marie-Laure Risse

Sanofi Oncology

Centre de Recherche de Vitry-Alfortville

13 quai Jules Guesde

94400 Vitry-sur-Seine

France

David P. Rotella

Montclair State University

Department of Chemistry & Biochemistry

1 Normal Ave

Montclair, NJ 07043

USA

Connie Sánchez

Lundbeck Research USA

Department of Neuroscience

215 College Road

Paramus, NJ 07652

USA

Dorothée Semiond

Sanofi

Centre de Recherche de Vitry-Alfortville

Department of Disposition, Safety and Animal Research (DSAR)

13 quai Jules Guesde

94400 Vitry-sur-Seine

France

Antonia F. Stepan

Pfizer Worldwide Research and Development

Neuroscience Medicinal Chemistry

700 Main Street

Cambridge, MA 02139

USA

Atsuhiro Sugidachi

Daiichi Sankyo Co., Ltd.

Biological Research Laboratories

1-2-58 Hiromachi, Shinagawa-ku

Tokyo 140-8710

Japan

Christian Tyrchan

AstraZeneca CV/GI

Lead Generation Department

Pepparedsleden 1

43150 Mölndal

Sweden

Joanne van Ryn

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Srikanth Venkatraman

Schering-Plough Research Institute

Department of Medicinal Chemistry

2015 Galloping Hill Road

Kenilworth, NJ 07033-1335

USA

Patricia Vrignaud

Sanofi Oncology

Centre de Recherche de Vitry-Alfortville

13 quai Jules Guesde

94400 Vitry-sur-Seine

France

Wolfgang Wienen

Boehringer Ingelheim Pharma GmbH & Co. KG

Department of Medicinal Chemistry

Birkendorfer Straße 65

88400 Biberach an der Riß

Germany

Part I

General Aspects

1

Pioneer and Analogue Drugs

János Fischer, C. Robin Ganellin, and David P. Rotella

A pioneer drug (“first in class”) represents a breakthrough invention that affords a marketed drug where no structurally and/or pharmacologically similar drug was known before its introduction. The majority of drugs, however, are analogue drugs, which have structural and/or pharmacological similarities to a pioneer drug or, as in some cases, to other analogue drugs.

The aim of this chapter is to discuss these two drug types [1].

The term “pioneer drug” is not used very often, because only a small fraction of drugs belongs to this type and in many cases the pioneer drugs lose their importance when similar but better drugs are discovered. A pioneer drug and its analogues form a drug class in which subsequent optimization may be observed. Analogue drugs typically offer benefits such as improved efficacy and/or side effect profiles or dose frequency than a pioneer drug to be successful on the market.

The discovery of both pioneer and analogue drugs needs some serendipity. A pioneer drug must clinically validate the safety and efficacy of a new molecular target and mechanism of action based on a novel chemical structure. In the case of an analogue drug, it is helpful that a pioneer or an analogue exists; nevertheless, some serendipity is needed to discover a new and better drug analogue, because there are no general guidelines on how such molecules can be identified preclinically. The analogue approach is very fruitful in new drug research, because there is a higher probability of finding a better drug than to discover a pioneer one. A significant risk with this approach is based on the potential for one of the many competitors in the drug discovery area to succeed prior to others.

The similarity between two drugs cannot be simply defined. Even a minor modification of a drug structure can completely modify the properties of a molecule. Levodopa (1) and methyldopa (2) are applied in different therapeutic fields; however, their structures differ only in a methyl group. Both molecules have the same stereochemistry as derivatives of l-tyrosine. Levodopa [2] is used for the treatment of Parkinson's disease as a dopamine precursor, whereas methyldopa [3] was an important antihypertensive agent before safer and more efficacious molecules (e.g., ACE inhibitors) appeared on the market.

Methyldopa (first synthesized at Merck Sharp & Dohme) has a dual mechanism of action: it is a competitive inhibitor of the enzyme DOPA decarboxylase and its metabolite acts as an α-adrenergic agonist.

Levodopa and methyldopa are not analogues from the viewpoint of medicinal chemistry. Both are pioneer drugs in their respective therapeutic fields and can be considered as stand-alone drugs, because they have no successful analogues.

There are several examples, and it is a usual case that a minor modification of a drug molecule affords a much more active drug in the same therapeutic field. The pioneer drug chlorothiazide (3) and its analogue hydrochlorothiazide (4) from Merck Sharp & Dohme differ only by two hydrogen atoms; however, the diuretic effect of hydrochlorothiazide [4] is 10 times higher than that of the original drug. The pioneer drug chlorothiazide is rarely used, but its analogue, hydrochlorothiazide, is an important first-line component in current antihypertensive therapy as a single agent and in combination with other compounds.

Chlorothiazide and hydrochlorothiazide are direct analogues, which term emphasizes their close relationship.

The terms “pioneer drugs” and “analogue drugs” will be discussed in the following sections.

1.1 Monotarget Drugs

1.1.1 H2 Receptor Histamine Antagonists

Before the launch of cimetidine (1976), only short-acting neutralization of gastric acid was possible by administration of various antacids (e.g., sodium bicarbonate, magnesium hydroxide, aluminum hydroxide, etc.) that did not affect gastric acid secretion. Cimetidine [5], the first successful H2 receptor histamine antagonist, a pioneer drug for the treatment of gastric hyperacidity and peptic ulcer disease, was discovered by researchers at Smith, Kline & French. The inhibition of histamine-stimulated gastric acid secretion was first studied in rats. Burimamide (5) was the first lead compound, a prototype drug, that also served as a proof of concept for inhibition of acid secretion in human subjects when administered intravenously, but its oral activity was insufficient. Its analogue, metiamide (6), was orally active, but its clinical studies had to be discontinued because of a low incidence of granulocytopenia. Replacing the thiourea moiety in metiamide with a cyanoguanidino moiety afforded cimetidine (7). Its use provided clinical proof for inhibition of gastric acid secretion and ulcer healing and was a great commercial and clinical success in the treatment of peptic ulcer disease.

Although cimetidine was very effective for the treatment of peptic ulcer disease and related problems of acid hypersecretion, there were some side effects associated with its use, albeit at a very low level. A low incidence of gynecomastia in men can occur at high doses of cimetidine due to its antiandrogen effect. Cimetidine also inhibits cytochrome P450, an important drug metabolizing enzyme. It is therefore advisable to avoid coadministration of cimetidine with certain drugs such as propranolol, warfarin, diazepam, and theophylline.

Cimetidine led to the initiation of analogue-based drug research affording more potent analogue drugs such as ranitidine (8) and famotidine (9) that lack the above side effects of cimetidine.

Ranitidine [6] also has a pioneer character, because ranitidine is the first H2 receptor histamine antagonist that has no antiandrogen adverse effect and does not inhibit the cytochrome CYP450 enzymes. Famotidine is the most potent member of this drug class, which has been discussed in Volume I of this series [7].

Summary:

Pioneer H2 receptor histamine antagonist: cimetidine.

First H2 receptor histamine antagonist with no antiandrogen adverse effects and without inhibition of P450 enzymes: ranitidine.

1.1.2 ACE Inhibitors

A natural product, the nonapeptide teprotide (10), was the pioneer drug for angiotensin-converting enzyme (ACE) inhibitors. Teprotide [8] was used as an active antihypertensive drug in patients with essential hypertension. It could only be administered parenterally, which is a great drawback for chronic use of a drug. A breakthrough occurred with the approval of the first orally active ACE inhibitor captopril (11) in 1980 by Squibb. Captopril [9] has a short onset time (0.5–1 h), and its duration of action is also relatively short (6–12 h); as a result, two to three daily doses are necessary. Captopril can be regarded as a pharmacological analogue of teprotide, but it is also the pioneer orally active ACE inhibitor. Captopril's discovery initiated intensive research by several other drug companies to discover longer acting ACE inhibitors. Enalapril (12) was introduced by Merck in 1984. Enalapril [10] can be regarded as the first long-acting oral ACE inhibitor. The long-acting ACE inhibitors are once-daily antihypertensive drugs. There are several long-acting ACE inhibitors, whose differences have been discussed in the first volume of this book series [11].

Summary:

Pioneer ACE inhibitor drug: teprotide.

First orally active ACE inhibitor drug: captopril.

First orally long-acting ACE inhibitor drug: enalapril.

1.1.3 DPP IV Inhibitors

Sitagliptin (13) [12], a pioneer dipeptidyl peptidase IV (DPP IV) inhibitor, was launched in 2006 by Merck for the treatment of type 2 diabetes. The medicinal chemistry team began its research in 1999 when some DPP IV inhibitor molecules were known as substrate-based analogues. The lead molecule derived from this research was vildagliptin (14) [13]; discovered at Novartis in 1998, it was the second compound to be introduced to the market.

The pioneer drug sitagliptin is a commercial success with 2010 sales greater than USD 3 billion. Vildagliptin was the first successful discovery in this drug class, but its development time was longer and it was introduced in 2007, after sitagliptin. Vildagliptin is only moderately selective over DPP-8 and DPP-9 compared to sitagliptin that is a highly selective DPP IV inhibitor. Based on long-term safety studies, these selectivity differences do not influence the toxicity of vildagliptin. Sitagliptin and vildagliptin show similar clinical efficacies. Vildagliptin has a short half-life (3 h) and its dosing regimen is twice a day, whereas sitagliptin has a long half-life (12 h) and once-daily dosing is used. DPP IV inhibitors are typical early-phase analogues that result from a highly competitive industry, and not the first candidate (vildagliptin) but a follow-on drug (sitagliptin) became the pioneer drug on the market (“first-in-class drug”). Further DPP IV inhibitors are available (alogliptin, saxagliptin, and linagliptin) and the individual compounds differ significantly in their mode of metabolism and excretion and these differences help the treatment of patients with type 2 diabetes in an individual way [14] (see Chapter 5 of Volume II of this book series).

Summary:

Pioneer DPP IV inhibitor drug: sitagliptin (long-acting inhibitor).

First DPP IV inhibitor analogue drug: vildagliptin (short-acting inhibitor).

1.1.4 Univalent Direct Thrombin Inhibitors

Thrombin is a serine protease enzyme whose inhibition plays an important role in the mechanism of several anticoagulants. Univalent direct thrombin inhibitors bind only to the active site of the enzyme, whereas bivalent direct thrombin inhibitors (e.g., hirudin and bivalirudin) block thrombin at both the active site and exosite 1.

The pioneer univalent direct thrombin inhibitor is argatroban monohydrate (15) [15] that was launched by Daiichi Pharmaceutical and Mitsubishi Pharma in 1990. Argatroban was approved by the FDA for prophylactic anticoagulation in the treatment of thrombosis in patients with heparin-induced thrombocytopenia. Argatroban is a rather selective reversible inhibitor for human thrombin. Despite its low molecular weight, argatroban is administered parenterally due to the presence of the highly basic guanidine moiety that prevents absorption from the gastrointestinal tract. This characteristic limits the clinical use of the compound. The first oral direct thrombin inhibitor was ximelagatran (17) [16], which was introduced in 2004 by AstraZeneca. Ximelagatran is a double prodrug derivative of melagatran (16) with a bioavailability of about 20%, a measurable improvement compared to melagatran with oral bioavailability of 5.8%. Ximelagatran was withdrawn from the market in 2006 because of unacceptable hepatic side effects (alanine aminotransferase increased threefold and bilirubin level increased twofold above the normal upper limit) [17]. In this drug class, dabigatran etexilate (18) [18] was discovered by Boehringer Ingelheim as a new direct thrombin inhibitor without adverse liver effects [19] (see Chapter 10)

Summary:

Pioneer univalent direct thrombin inhibitor drug: argatroban.

First orally active univalent thrombin inhibitor: ximelagatran.

First orally active univalent thrombin inhibitor without adverse liver affects: dabigatran etexilate.

1.2 Dual-Acting Drugs

1.2.1 Monotarget Drugs from Dual-Acting Drugs

1.2.1.1 Optimization of Beta-Adrenergic Receptor Blockers

James W. Black and coworkers at ICI invented propranolol as a product of analogue-based drug discovery (ABDD) using their prototype drug, pronethalol (19), as a lead compound. Pronethalol [20] was an active drug for the treatment of angina pectoris in humans, but its development was discontinued because it proved to be carcinogenic in mice in long-term toxicology studies. Continuation of the analogue-based drug discovery afforded propranolol (20), where an oxymethylene link was inserted between the 1-napthyl group and the secondary alcohol moiety of pronethalol. Propranolol [21] was more potent than pronethalol. Propranolol became the pioneer nonselective β-adrenergic receptor antagonist, a true antagonist without partial agonist properties (intrinsic sympathomimetic activity). It was a breakthrough discovery for the treatment of arrhythmias, angina pectoris, and hypertension.

The pioneer drug propranolol has equal antagonist affinity for β1 and β2 adrenergic receptors; however, β1 receptors are located only in the heart and the nonselective propranolol also blocks β2 receptors in bronchial smooth muscle. Therefore, propranolol is not used in patients with bronchial asthma. Several analogues have been tested in a battery of in vivo pharmacological tests resulting in the discovery of atenolol (21) [22]. A guinea pig bronchospasm test served for investigation and demonstration of β1 selectivity. Atenolol had no intrinsic sympathomimetic effect (partial agonism), similar to propranolol (see Chapter 8 of Volume I (Part II) of this book series).

Summary:

Pioneer dual-acting (β1 and β2) beta-adrenergic receptor antagonist: propranolol.

First β1 selective antagonist drug without intrinsic sympathomimetic activity: atenolol.

1.2.2 Dual-Acting Drugs from Monotarget Drugs

1.2.2.1 Dual-Acting Opioid Drugs

Most ligands designed from the morphine template are mu (µ) opioid receptor (MOP) agonists. A simplified version of the morphine skeleton afforded tramadol that is marketed in its racemic form. The (+)-isomer is a weak MOP agonist, whereas the (−)-isomer inhibits neurotransmitter reuptake. Tramadol (22) [23] was discovered by Grünenthal and was introduced in 1977 for the treatment of moderate to severe pain.

Grünenthal continued analogue-based drug research using tramadol as a starting compound, and out of several analogues, tapentadol (23) [24] was selected and developed. It was introduced in 2009 to the market as a new opioid analgesic drug with dual activity: a MOP agonist and an inhibitor of norepinephrine reuptake. Tramadol is thousands of times less potent than morphine on the mu opioid receptor, whereas tapentadol's analgesic activity is comparable to that of oxycodone with reduced constipation and respiratory depression (see Chapter 12).

Summary:

Pioneer dual-acting (MOP agonist and norepinephrine reuptake inhibitor) opioid drug racemate: tramadol.

First dual-acting (MOP agonist and norepinephrine reuptake inhibitor) opioid drug in a single molecule: tapentadol.

1.3 Multitarget Drugs

1.3.1 Multitarget Drug Analogue to Eliminate a Side Effect

1.3.1.1 Clozapine and Olanzapine

Clozapine (24) [25] is the pioneer drug in the class of atypical antipsychotic agents. It was a serendipitous discovery by researchers at Wander in Switzerland in 1960 from the structural analogue antidepressant amoxapine (25). Its discovery was unexpected from the structurally very close analogue and therapeutically it had a great advantage over the typical antipsychotic drugs such as chlorpromazine and haloperidol because clozapine produced no extrapyramidal side effects (EPS). Clozapine causes agranulocytosis in about 1% of the patients, and this side effect limited its application. Analogue-based drug design afforded quetiapine (26) [26], a clozapine analogue without this side effect. It was discovered at ICI in 1986 and it became one of the main products of AstraZeneca. Instead of the dibenzodiazepine nucleus of clozapine, the analogue quetiapine has a dibenzothiazepine scaffold. Both clozapine and quetiapine have affinity for a number of receptors. The antipsychotic activity is believed to be associated primarily by virtue of affinity for D2 and 5-HT2A receptors. Chapter 3 discusses metabolic aspects that may contribute to the distinct adverse event profiles of these two drugs (see the chapter of Volume I on clozapine analogues).

Summary:

Pioneer atypical antipsychotic drug: clozapine.

First atypical clozapine-like antipsychotic drug without the side effect of agranulocytosis: quetiapine.

1.3.2 Selective Drug Analogue from a Pioneer Multitarget Drug

1.3.2.1 Selective Serotonin Reuptake Inhibitors

From a retrospective viewpoint, imipramine (27) was the pioneer antidepressant drug with a multitarget receptor profile, where serotonin and norepinephrine reuptake inhibition played an important role, but no in vitro activities were known at the time of its serendipitous discovery. Researchers at Geigy first synthesized the molecule in 1948. It was an analogue of the antipsychotic chlorpromazine (28), but the Swiss psychiatrist Roland Kuhn [27] found imipramine to be an effective antidepressant drug. It was launched by Geigy in 1959.

Imipramine and the analogue tricyclic antidepressants inhibit the reuptake of serotonin and norepinephrine but they also exhibit a variety of side effects. The anticholinergic side effects include dry mouth, blurred vision, and sinus tachycardia. The histamine H1 receptor antagonist activity likely contributes to the sedative effects associated with the compound.

Arvid Carlsson initiated research on selective serotonin reuptake inhibitors (SSRIs) in order to get new antidepressants with less side effects. The first SSRI was zimelidine (29) [28]. It was launched by Astra in 1982, but it had to be withdrawn shortly afterward because of serious peripheral nerve side effects. Further research was continued at several pharmaceutical companies. The first successful SSRIs were fluoxetine (30) [29] (Lilly, 1988) and citalopram (31) [30] (Lundbeck, 1989). The antihistamine diphenhydramine (32) served as a lead compound for fluoxetine, whereas talopram (33) was the lead structure for citalopram. The discovery of citalopram and its refinement to escitalopram is discussed in Chapter 11.

Summary:

Pioneer multitarget nonselective serotonin/norepinephrine reuptake inhibitor antidepressant drug: imipramine.

First (but unsuccessful) selective serotonin reuptake inhibitor: zimelidine.

First selective serotonin reuptake inhibitors: fluoxetine and citalopram.

1.4 Summary

Pioneer drugs open up new therapeutic treatments. They are also called “first-in-class” drugs.

Analogue-based drug discovery is a very important part of medicinal chemistry, because the analogues frequently are intended to optimize drug therapy. There is a continuous development in a drug class and in several cases the pioneer drugs disappear from the market and analogue drugs achieve a dominant role. It is the main reason why so many successful drugs are among the analogue drugs. The above examples focused on some cases where these drugs have a unique character in a drug class.

For early-phase analogues, it is possible that a pioneer drug derives from the analogue-based drug discovery for different reasons; for example, a more convenient lead compound or a more successful optimization can strongly influence which drug will be introduced to the market as a pioneer drug.

There are several examples where a new prototype drug candidate was discontinued at the late phase of drug research and then an analogue was introduced to the market as a successful pioneer drug.

The properties of pioneer and analogue drugs overlap (Figure 1.1). The drug analogues preserve some properties of the pioneer drug and they have to achieve some new and better properties in order to be successful on the market.

Figure 1.1 Pioneer drugs and drug analogues have overlapping properties.

Acknowledgments

We thank Klaus Peter Bøgesø, Helmut Buschmann, Jens-Uwe Peters, and Henning Priepke for carefully reading and reviewing the manuscript.

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János Fischer is Senior Research Scientist at Richter Plc. (Budapest, Hungary). He received his education in Hungary with M.Sc. and Ph.D. degrees in Organic Chemistry from Eotvos University of Budapest with Professor A. Kucsman. Between 1976 and 1978, he was a Humboldt Fellow at the University of Bonn with Professor W. Steglich. He has worked at Richter Plc. since 1981, where he participated in the research and development of leading cardiovascular drugs in Hungary. His main current interest is analogue-based drug discovery. He is author of some 100 patents and scientific publications. In 2012, he was reelected Titular Member of the Chemistry and Human Health Division of IUPAC. He received an honorary professorship at the Technical University of Budapest.

C. Robin Ganellin studied chemistry at London University, receiving a Ph.D. in 1958 under Professor Michael Dewar, and was a Research Associate at MIT with Arthur Cope in 1960. He then joined Smith, Kline & French Laboratories in the United Kingdom and was one of the co-inventors of the revolutionary drug cimetidine (also known as Tagamet®), eventually becoming Vice President for Research. In 1986, he was made a Fellow of the Royal Society and appointed to the SK&F Chair of Medicinal Chemistry at University College London, where he is now Professor Emeritus of Medicinal Chemistry. Professor Ganellin is co-inventor on over 160 patents and has authored over 250 scientific publications. He was President of the Medicinal Chemistry Section of IUPAC and is currently Chairman of the IUPAC Subcommittee on Medicinal Chemistry and Drug Development.

David P. Rotella is the Margaret and Herman Sokol Professor of Medicinal Chemistry at Montclair State University. He earned a B.S. Pharm. degree at the University of Pittsburgh (1981) and a Ph.D. (1985) at The Ohio State University with Donald. T. Witiak. After postdoctoral studies in organic chemistry at Penn State University with Ken S. Feldman, he worked as an Assistant Professor at the University of Mississippi. David worked at Cephalon, Bristol-Myers, Lexicon, and Wyeth, where he was involved in neurodegeneration, schizophrenia, cardiovascular, and metabolic disease drug discovery projects.

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Competition in the Pharmaceutical Drug Development