Bioactive Carboxylic Compound Classes

Following the successful and proven concept used in "Bioactive Heterocyclic Compound Classes" by the same editors, this book is the first to present approved pharmaceutical and agrochemical compounds classified by their carboxylic acid functionality in one handy volume. Each of the around 40 chapters describes one or two typical syntheses of a specific compound class and provides concise information on the history of development, mode of action, biological activity and field of application, as well as structure-activity relationships. In addition, similarities and differences between pharmaceuticals and agrochemicals are discussed in the introduction. Written by a team of experts in the field, this is a useful reference for researchers in academia and chemical or pharmaceutical companies working in the field of total synthesis and natural product chemistry, drug development, and crop protection research.

Auteur
Clemens Lamberth is a senior team leader in the crop protection research department of Syngenta AG, Switzerland. He studied chemistry at the Technical University of Darmstadt, Germany, where he obtained his Ph.D. under the supervision of Prof. Bernd Giese in 1990. Subsequently, he spent one and a half years as a postdoctoral fellow in the group of Prof. Mark Bednarski at the University of California at Berkeley, USA. In 1992 he joined the agrochemical research department of Sandoz Agro AG, Switzerland, which is today, after two mergers, part of Syngenta Crop Protection AG. Since 22 years he is specialized in fungicide discovery. He is the author of more than 130 publications and patents and inventor of Syngenta's fungicide mandipropamid (Revus?, Pergado?).

Jurgen Dinges is a senior principal research scientist in the pharmaceutical research department at Abbvie, USA. He studied chemistry at the Technical University of Darmstadt, Germany, where he obtained his Ph.D. degree in organic chemistry and chemical engineering under the supervision of Prof. Frieder W. Lichtenthaler in 1991. After being awarded a Feodor-Lynen scholarship from the Humboldt foundation, he spent 18 months as a postdoctoral fellow in the group of Prof. William G. Dauben at the University of California at Berkeley, USA. In 1993 he joined the Department for Biochemistry at Syntex, USA, which today is part of Hoffmann-La Roche Ltd., Switzerland. In 1995 he joined the pharmaceutical research department at Abbott Laboratories, USA, which became part of Abbvie in 2013. Since 19 years he is specialized in drug discovery. He is an author on 57 publications and patents and a co-inventor of more than 10 clinical drug development candidates.

Contenu

List of Contributors XV

Preface XXI

1 Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals 1
Clemens Lamberth and Jürgen Dinges

1.1 Introduction 1

1.2 Solubilizer 1

1.3 Pharmacophore 3

1.4 Prodrug 4

1.5 Bioisosteric Replacement 6

1.6 Scaffold 8

1.7 Conclusion 9

Part I Neurology 13

2 Carboxylic Ester Containing NorepinephrineDopamine Reuptake Inhibitors (NDRIs) 15
David J. O'Neill

2.1 Introduction 15

2.2 History 15

2.3 Synthesis 17

2.4 Mode of Action 21

2.5 StructureActivity Relationships 22

3 Analgesic and Anesthetic Amides 27
Thomas Erhard

3.1 Introduction 27

3.2 History 27

3.3 Synthesis 30

3.4 Mode of Action 33

3.5 StructureActivity Relationships 34

Part II Cardiovascular Diseases 39

4 Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPAR Activators) 41
Gavin O'Mahony

4.1 Introduction 41

4.2 History 42

4.3 Synthesis 45

4.4 Mode of Action 48

4.5 StructureActivity Relationships 50

5 Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events 57
Modesto de Candia, Nunzio Denora, and Cosimo D. Altomare

5.1 Introduction 57

5.2 History 57

5.3 Synthesis 60

5.4 Mode of Action 62

5.5 StructureActivity Relationships 67

6 Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors 71
Xiang-Yang Ye and Pratik Devasthale

6.1 Introduction 71

6.2 History 72

6.3 Synthesis 73

6.4 Mode of Action 80

6.5 StructureActivity Relationship 81

7 Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease 87
Steve Swann and Simone Bigi

7.1 Introduction 87

7.2 History 89

7.3 Synthesis 90

7.4 Mode of Action 95

7.5 StructureActivity Relationships 96

8 Carboxylic Acid Containing Direct Thrombin Inhibitors for the Treatment of Thromboembolic Diseases 103
Harry R. Chobanian and Mathew M. Yanik

8.1 Introduction 103

8.2 History 104

8.3 Synthesis 106

8.4 Mode of Action 108

8.5 StructureActivity Relationship 109

Part III Infectious Diseases 115

9 Tetracycline Amide Antibiotics 117
Ingo Janser

9.1 Introduction 117

9.2 History 120

9.2.1 First-Generation Tetracyclines The Discovery 120

9.2.2 Second-Generation Semisynthetic Tetracyclines 121

9.2.3 Tetracycline Resistance 122

9.2.4 Third-Generation Tetracyclines 123

9.3 Synthesis 123

9.4 Mode of Action 127

9.5 StructureActivity Relationships 128

10 Carboxylic-Acid-Based Neuraminidase Inhibitors 133
Stacy Van Epps

10.1 Introduction 133

10.2 History 133

10.3 Synthesis 136

10.4 Mode of Action 142

10.5 StructureActivity Relationships 143

11 Oxazolidinone Amide Antibiotics 149
Cristiana A. Zaharia, Saverio Cellamare, and Cosimo D. Altomare

11.1 Introduction 149

11.2 History 150

11.3 Synthesis 153

11.4 Mechanism of Action 156

11.5 StructureActivity Relationships 162 12 Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester Used for the Treatment of Hepatitis C Infection 167
*Alastair Donald...