Bioactive Carboxylic Compound Classes

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®). Jürgen 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.

• List of Contributors XVPreface XXI1 Different Roles of Carboxylic Functions in Pharmaceuticals and Agrochemicals 1Clemens Lamberth and Jürgen Dinges1.1 Introduction 11.2 Solubilizer 11.3 Pharmacophore 31.4 Prodrug 41.5 Bioisosteric Replacement 61.6 Scaffold 81.7 Conclusion 9Part I Neurology 132 Carboxylic Ester Containing Norepinephrine–Dopamine Reuptake Inhibitors (NDRIs) 15David J. O'Neill2.1 Introduction 152.2 History 152.3 Synthesis 172.4 Mode of Action 212.5 Structure–Activity Relationships 223 Analgesic and Anesthetic Amides 27Thomas Erhard3.1 Introduction 273.2 History 273.3 Synthesis 303.4 Mode of Action 333.5 Structure–Activity Relationships 34Part II Cardiovascular Diseases 394 Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators) 41Gavin O'Mahony4.1 Introduction 414.2 History 424.3 Synthesis 454.4 Mode of Action 484.5 Structure–Activity Relationships 505 Antiplatelet 2-Hydroxy Thienopyridine Ester Derivatives for the Reduction of Thrombotic Cardiovascular Events 57Modesto de Candia, Nunzio Denora, and Cosimo D. Altomare5.1 Introduction 575.2 History 575.3 Synthesis 605.4 Mode of Action 625.5 Structure–Activity Relationships 676 Carboxylic Acids and Lactones as HMG-CoA Reductase Inhibitors 71Xiang-Yang Ye and Pratik Devasthale6.1 Introduction 716.2 History 726.3 Synthesis 736.4 Mode of Action 806.5 Structure–Activity Relationship 817 Angiotensin II Receptor Antagonists with Carboxylic Functionalities in Cardiovascular Disease 87Steve Swann and Simone Bigi7.1 Introduction 877.2 History 897.3 Synthesis 907.4 Mode of Action 957.5 Structure–Activity Relationships 968 Carboxylic Acid Containing Direct Thrombin Inhibitors for the Treatment of Thromboembolic Diseases 103Harry R. Chobanian and Mathew M. Yanik8.1 Introduction 1038.2 History 1048.3 Synthesis 1068.4 Mode of Action 1088.5 Structure–Activity Relationship 109Part III Infectious Diseases 1159 Tetracycline Amide Antibiotics 117Ingo Janser9.1 Introduction 1179.2 History 1209.2.1 First-Generation Tetracyclines – The Discovery 1209.2.2 Second-Generation Semisynthetic Tetracyclines 1219.2.3 Tetracycline Resistance 1229.2.4 Third-Generation Tetracyclines 1239.3 Synthesis 1239.4 Mode of Action 1279.5 Structure–Activity Relationships 12810 Carboxylic-Acid-Based Neuraminidase Inhibitors 133Stacy Van Epps10.1 Introduction 13310.2 History 13310.3 Synthesis 13610.4 Mode of Action 14210.5 Structure–Activity Relationships 14311 Oxazolidinone Amide Antibiotics 149Cristiana A. Zaharia, Saverio Cellamare, and Cosimo D. Altomare11.1 Introduction 14911.2 History 15011.3 Synthesis 15311.4 Mechanism of Action 15611.5 Structure–Activity Relationships 16212 Sovaldi, an NS5B RNA Polymerase-Inhibiting Carboxylic Acid Ester Used for the Treatment of Hepatitis C Infection 167Alastair Donald12.1 Introduction 16712.2 History 16812.3 Synthesis 17012.4 Mode of Action 17212.5 Structure–Activity Relationships 173Part IV Metabolic Diseases 17713 Dipeptidyl Peptidase-4 (DPP-4)-Inhibiting Amides for the Treatment of Diabetes 179Naomi S. Rajapaksa and Xiaodong Lin13.1 Introduction 17913.2 History 17913.3 Synthesis 18413.4 Mode of Action 18713.5 Structure–Activity Relationships 188Part V Oncology 19714 Ibrutinib, a Carboxylic Acid Amide Inhibitor of Bruton's Tyrosine Kinase 199Timothy D. Owens14.1 Introduction 19914.2 History 19914.3 Synthesis 20114.4 Mechanism of Action 20214.5 Structure–Activity Relationships 203Part VI Anti-Inflammatory Drugs 20915 Fumaric Acid Esters 211Tony S. Gibson15.1 Introduction 21115.2 History 21115.3 Synthesis 21315.4 Mode of Action 21315.5 Structure–Activity Relationships 21516 Carboxylic Acid Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) 221Yan Lou and Jiang Zhu16.1 Introduction 22116.2 History 22216.3 Synthesis 22416.4 Mode of Action 22816.5 Structure–Activity Relationships 23017 Carboxylic-Acid-Containing Antihistamines 237Irini Akritopoulou-Zanze17.1 Introduction 23717.2 History 23717.3 Synthesis 23917.4 Mode of Action 24117.5 Structure–Activity Relationship 24118 Corticosteroid Carboxylic Acid Esters 245Maurizio Franzini18.1 Introduction 24518.2 History 24918.3 Synthesis 25218.4 Mode of Action 25818.5 Structure–Activity Relationships 261Part VII Ophthalmology 26919 Prostaglandins with Carboxylic Functionalities for the Treatment of Glaucoma 271Fabrizio Carta and Claudiu T. Supuran19.1 Introduction 27119.2 History 27119.3 Synthesis 27219.4 Mode of Action 27619.5 Structure–Activity–Relationship (SAR) 278Part VIII Weed Control 28120 Herbicidal Carboxylic Acids as Synthetic Auxins 283Paul Schmitzer, Jeffrey Epp, Roger Gast,William Lo, and Jeff Nelson20.1 Introduction 28320.2 History 28320.3 Synthesis 28620.4 Mode of Action 28920.5 Biological Activity 28921 Chloroacetamide Herbicides 293Clemens Lamberth21.1 Introduction 29321.2 History 29321.3 Synthesis 29621.4 Mode of Action 29721.5 Biological Activity 29921.6 Structure–Activity Relationship 30022 Carboxylic-Acid-Containing Sulfonylurea Herbicides 303Atul Puri and Paul H. Liang22.1 Introduction 30322.2 History 30322.3 Synthesis 30522.4 Mode of Action 30622.5 Biological Activity 30822.6 Structure–Activity Relationship 30923 Amino Acids as Nonselective Herbicides 315Stephane Jeanmart23.1 Introduction 31523.2 History 31623.3 Synthesis 31723.4 Mode of Action 31923.5 Biological Activity 32023.6 Structure–Activity Relationships 32124 Herbicidal Aryloxyphenoxypropionate Inhibitors of Acetyl-CoA Carboxylase 325William G.Whittingham24.1 Introduction 32524.2 History 32524.3 Synthesis 32724.4 Mode of Action 32924.5 Biological Activity 33024.6 Structure–Activity Relationships 33125 Pyridines Substituted by an Imidazolinone and a Carboxylic Acid as Acetohydroxyacid-Synthase-Inhibiting Herbicides 339Dale Shaner25.1 Introduction 33925.2 History 33925.3 Synthesis 34125.4 Mode of Action 34225.5 Biological Activity 34225.6 Structure–Activity Relationship 34426 Carboxylic-Acid-Containing Protoporphyrinogen-IX-Oxidase-Inhibiting Herbicides 347George Theodoridis26.1 Introduction 34726.2 History 34726.3 Synthesis 35026.4 Mode of Action 35126.5 Biological Activity 35226.6 Structure–Activity Relationship 352Part IX Disease Control 35727 Phenylamide Fungicides 359Laura Quaranta27.1 Introduction 35927.2 History 35927.3 Synthesis 36227.4 Mode of Action 36427.5 Biological Activity 36527.6 Structure–Activity Relationship 36528 Complex III Inhibiting Strobilurin Esters, Amides, and Carbamates as Broad-Spectrum Fungicides 371Clemens Lamberth28.1 Introduction 37128.2 History 37128.3 Synthesis 37528.4 Mode of Action 37928.5 Biological Activity 38028.6 Structure–Activity Relationship 38129 Scytalone-Dehydratase-Inhibiting Carboxamides for the Control of Rice Blast 385Andrew E. Taggi29.1 Introduction 38529.2 History 38529.3 Synthesis 38929.4 Mode of Action 39029.5 Biological Activity 39129.6 Structure–Activity Relationships 39230 Carboxylic Acid Amide Fungicides for the Control of Downy Mildew Diseases 395Clemens Lamberth30.1 Introduction 39530.2 History 39530.3 Synthesis 39730.4 Mode of Action 39930.5 Biological Activity 40030.6 Structure–Activity Relationship 40031 Fungicidal Succinate-Dehydrogenase-Inhibiting Carboxamides 405Harald Walter31.1 Introduction 40531.2 History 40631.3 Synthesis 40931.4 Mode of Action and Importance of Respiration Inhibitors 41531.5 Biological Activity and Market Impact 41631.6 Structure–Activity Relationships 418Part X Insect Control 42732 Esters and Carbamates as Insecticidal Juvenile Hormone Mimics 429Sebastian Rendler32.1 Introduction 42932.2 History 42932.3 Synthesis 43132.4 Mode of Action 43332.5 Biological Activity 43432.6 Structure–Activity Relationship 43433 N-Benzoyl-N′-Phenyl Ureas as Insecticides, Acaricides, and Termiticides 439Peter Jeschke33.1 Introduction 43933.2 History 43933.3 Synthesis 44233.4 Mode of Action 44533.5 Biological Activity 44633.6 Structure–Activity Relationship 44834 Pyrethroid Esters for the Control of Insect Pests 453Régis Mondière and Fides Benfatti34.1 Introduction 45334.2 History 45434.3 Synthesis 45734.4 Mode of Action 45934.5 Biological Activity 46134.6 Structure–Activity Relationship 46235 Ecdysone Receptor Agonistic Dibenzoyl Hydrazine Insecticides 467Ottmar F. Hüter35.1 Introduction 46735.2 History 46735.3 Synthesis 46835.4 Mode of Action 47135.5 Biological Activity 47335.6 Structure–Activity Relationship 47336 Diamide Insecticides as Ryanodine Receptor Activators 479André Jeanguenat36.1 Introduction 47936.2 History 47936.3 Synthesis 48136.4 Mode of Action 48536.5 Biological Activity 48536.6 Structure–Activity Relationship 486Index 491