Annual Reports in Medicinal Chemistry

1. Auflage 2014
ISBN: 978-0-12-800372-5
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 49, 636 Seiten

Reihe: Annual Reports in Medicinal Chemistry

Annual Reports in Medicinal Chemistry provides timely and critical reviews of important topics in medicinal chemistry with an emphasis on emerging topics in the biological sciences that are expected to provide the basis for entirely new future therapies. - Reviews on hot topics of interest in small molecule drug discovery heavily pursued by industrial research organizations - Provides preclinical information in the context of chemical structures - Knowledgeable section editors who evaluate invited reviews for scientific rigor

Autoren/Hrsg.

Inhaltsverzeichnis

1;Front Cover;1
2;Annual Reports in Medicinal Chemistry;4
3;Copyright;5
4;Contents;6
5;Contributors;16
6;Preface;18
7;Personal Essays;20
7.1;Chapter One: A Personal Essay: My Experiences in the Pharmaceutical Industry;22
7.1.1;References;27
7.2;Chapter Two: Adventures in Medicinal Chemistry: A Career in Drug Discovery;30
7.2.1;Acknowledgments;40
7.2.2;References;40
8;Section 1: Central Nervous System Diseases;44
8.1;Chapter Three: Natural and Synthetic Neuroactive Steroid Modulators of GABAA and NMDA Receptors;46
8.1.1;1. Introduction;46
8.1.2;2. NAS Modulators of the GABAA Receptor;48
8.1.2.1;2.1. Endogenous NAS Modulators of the GABAA Receptor;50
8.1.2.2;2.2. Synthetic NAS Modulators of the GABAA Receptor;51
8.1.2.2.1;2.2.1. Anesthetics;51
8.1.2.2.2;2.2.2. Compounds Suitable for Nonanesthetic Indications;53
8.1.3;3. NAS Modulators of the NMDA Receptor;55
8.1.4;4. Conclusions;57
8.1.5;References;58
8.2;Chapter Four: Development of LRRK2 Kinase Inhibitors for Parkinson´s Disease;62
8.2.1;1. Introduction;62
8.2.2;2. LRRK2 Biology;63
8.2.3;3. Medicinal Chemistry;65
8.2.3.1;3.1. LRRK2 Patent Space Analysis;66
8.2.3.2;3.2. Chemical Scaffolds;67
8.2.3.2.1;3.2.1. Repurposed Kinase Inhibitors;69
8.2.3.2.2;3.2.2. First-Generation LRRK2-Focused Kinase Inhibitors;70
8.2.3.2.3;3.2.3. Second-Generation LRRK2-Focused Kinase Inhibitors;70
8.2.3.2.4;3.2.4. Third-Generation LRRK2-Focused Kinase Inhibitors;72
8.2.4;4. Preclinical Animal Models;73
8.2.5;5. Conclusions;74
8.2.6;References;74
8.3;Chapter Five: Stimulating Neurotrophin Receptors in the Treatment of Neurodegenerative Disorders;78
8.3.1;1. Introduction;78
8.3.2;2. NTs and NT Receptors-Structure and Function;79
8.3.3;3. Role of NTs and Their Receptors in Neurodegenerative Disorders;80
8.3.4;4. Pharmacological Activators of NT Receptors;81
8.3.4.1;4.1. Peptidic Activators;81
8.3.4.2;4.2. Small-Molecule Activators;82
8.3.5;5. Conclusion;90
8.3.6;References;90
9;Section 2: Cardiovascular and Metabolic Diseases;94
9.1;Chapter Six: Small-Molecule Modulators of GPR40 (FFA1);96
9.1.1;1. Introduction;96
9.1.2;2. Recent Discoveries in GPR40 Biology;97
9.1.3;3. GPR40 Partial Agonists;98
9.1.3.1;3.1. TAK-875;98
9.1.3.2;3.2. AMG 837;99
9.1.3.3;3.3. LY2881835;100
9.1.4;4. GPR40 Full Agonists;101
9.1.5;5. Conclusions;103
9.1.6;References;104
9.2;Chapter Seven: Recent Advances in the Development of P2Y12 Receptor Antagonists as Antiplatelet Agents;106
9.2.1;1. Introduction;106
9.2.2;2. FDA-Approved P2Y12 Receptor Antagonists;107
9.2.2.1;2.1. Thienopyridines;108
9.2.2.2;2.2. ATP Analogs;109
9.2.3;3. New P2Y12 Receptor Antagonists;109
9.2.3.1;3.1. ATP Analogs;109
9.2.3.2;3.2. Thienopyridines;111
9.2.3.3;3.3. Miscellaneous Scaffolds;112
9.2.3.3.1;3.3.1. Phenylpyrazole Glutamic Acid Piperazines;112
9.2.3.3.2;3.3.2. 6-Aminonicotinates;113
9.2.4;4. Clinical Application;114
9.2.5;5. Conclusions;116
9.2.6;References;116
9.3;Chapter Eight: Current Approaches to the Treatment of Atrial Fibrillation;120
9.3.1;1. Introduction;120
9.3.2;2. Atrial-Selective Agents Versus Non-selective Agents;121
9.3.2.1;2.1. Current Standard of Care;121
9.3.2.2;2.2. Mechanism and Atrial-Specific Ion Channels;122
9.3.3;3. Clinical Updates;122
9.3.3.1;3.1. Non-selective Agents;122
9.3.3.2;3.2. Atrial-Selective Agents;123
9.3.3.2.1;3.2.1. IKur Inhibitors;123
9.3.3.2.2;3.2.2. IKAch Inhibitors;124
9.3.4;4. Preclincal Advances;124
9.3.4.1;4.1. IKur Inhibitors;124
9.3.4.1.1;4.1.1. Thienopyrimidines and Thienopyrazoles;124
9.3.4.1.2;4.1.2. Imidazolidinones;125
9.3.4.1.3;4.1.3. Indazole and Pyrrolopyrimidines;125
9.3.4.1.4;4.1.4. Phenylsulfonamides;126
9.3.4.1.5;4.1.5. Phenylcyclohexanes and gem-Dimethyl Isoindolinone;128
9.3.4.1.6;4.1.6. Benzodiazepines;128
9.3.4.2;4.2. IKAch Inhibitors;129
9.3.4.2.1;4.2.1. Benzamides;129
9.3.5;5. Conclusion;129
9.3.6;References;130
10;Section 3: Inflammation/Pulmonary/GI Diseases;134
10.1;Chapter Nine: Advances in the Discovery of Small-Molecule IRAK4 Inhibitors;136
10.1.1;1. Introduction;136
10.1.2;2. Rationale for Targeting IRAK4 in Inflammatory Diseases;137
10.1.2.1;2.1. TLR and IL-1R Signaling;137
10.1.2.2;2.2. Human IRAK4-Deficient Patients;137
10.1.2.3;2.3. Genetic Validation;138
10.1.2.4;2.4. TLR and IL-1-Targeted Therapies;138
10.1.2.5;2.5. IRAK4 and Cancer;139
10.1.3;3. IRAK4 Structure;139
10.1.4;4. Recent Medicinal Chemistry Efforts;140
10.1.4.1;4.1. Benzimidazoles;140
10.1.4.2;4.2. Thiazole, Pyridyl, and Oxazole Amides;142
10.1.4.3;4.3. Pyrazolo and Thiophene Fused Pyrimidine Amides;143
10.1.4.4;4.4. Pyridyl Amines;144
10.1.4.5;4.5. 6,5-Fused Tricyclic Thienopyrimidines and Related Heterocycles;145
10.1.4.6;4.6. Other Heterocyclic Cores;147
10.1.5;5. Conclusions;149
10.1.6;References;149
10.2;Chapter Ten: H4 Receptor Antagonists and Their Potential Therapeutic Applications;154
10.2.1;1. Introduction;154
10.2.1.1;1.1. Histamine Receptor Family;154
10.2.1.2;1.2. Expression and Function of the Histamine H4 Receptor;155
10.2.2;2. Antagonists of the H4 Receptor;155
10.2.2.1;2.1. Indole and Benzimidazole Amide Ligands;155
10.2.2.2;2.2. Dibenzodiazepine, Quinoxalinone, and Quinazoline Ligands;156
10.2.2.3;2.3. Pyrimidine-Based Ligands;157
10.2.3;3. Role of the Histamine H4 Receptor in Disease Models;163
10.2.3.1;3.1. Acute Inflammation and Inflammatory Pain;163
10.2.3.2;3.2. Rheumatoid Arthritis;163
10.2.3.3;3.3. Asthma;164
10.2.3.4;3.4. Pruritis;164
10.2.4;4. Clinical Development of H4 Receptor Antagonists;165
10.2.5;5. Conclusions;165
10.2.6;References;165
10.3;Chapter Eleven: Urate Crystal Deposition Disease and Gout-New Therapies for an Old Problem;170
10.3.1;1. Introduction;170
10.3.2;2. Therapeutics for Gout by Clinical Manifestation;172
10.3.2.1;2.1. Gout Flares;172
10.3.2.1.1;2.1.1. Nonsteroidal Anti-Inflammatory Drugs;173
10.3.2.1.2;2.1.2. Colchicine;173
10.3.2.1.3;2.1.3. Glucocorticoids;173
10.3.2.1.4;2.1.4. IL-1 Blockade;174
10.3.2.1.5;2.1.5. Phosphodiesterase-4;174
10.3.2.1.6;2.1.6. Anti-C5a Antibody;175
10.3.2.1.7;2.1.7. CXCR2;175
10.3.2.2;2.2. Hyperuricemia;175
10.3.2.2.1;2.2.1. Drugs Blocking Uric Acid Production;176
10.3.2.2.1.1;2.2.1.1. XO Inhibition;177
10.3.2.2.1.2;2.2.1.2. Purine Nucleoside Phosphorylase Inhibition;178
10.3.2.2.1.3;2.2.1.3. Concentrative Nucleoside Transporter Type 2;178
10.3.2.2.2;2.2.2. Drugs Increasing Uric Acid Excretion;179
10.3.2.2.3;2.2.3. Drugs Catalyzing Uric Acid Metabolism;181
10.3.3;3. Conclusions;181
10.3.4;References;182
11;Section 4: Oncology;184
11.1;Chapter Twelve: p53-MDM2 and MDMX Antagonists;186
11.1.1;1. Introduction;186
11.1.1.1;1.1. Importance of p53/MDM2/MDMX in Tumor Suppression (p53 Pathway Regulation);187
11.1.1.2;1.2. The p53/MDM2/MDMX Interaction (Crystal Structures);187
11.1.2;2. MDM2 Antagonists;188
11.1.2.1;2.1. Nutlin-Type Compounds;188
11.1.2.2;2.2. Imidazoles;189
11.1.2.3;2.3. Imidazothiazoles;190
11.1.2.4;2.4. Benzodiazepines;191
11.1.2.5;2.5. Spirooxindoles;192
11.1.2.6;2.6. Isoindolones;192
11.1.2.7;2.7. Indole-2-Carboxylic Acid Derivatives;193
11.1.2.8;2.8. Pyrrolidinones;194
11.1.2.9;2.9. Pyrrolidines;195
11.1.2.10;2.10. Isoquinolines and Piperidinones;196
11.1.2.11;2.11. Peptides;197
11.1.2.12;2.12. Miscellaneous Compounds;198
11.1.3;3. MDMX Antagonists;199
11.1.3.1;3.1. Imidazoles;199
11.1.3.2;3.2. Miscellaneous Compounds;200
11.1.4;4. Conclusion;202
11.1.5;References;203
11.2;Chapter Thirteen: Modulators of Atypical Protein Kinase C as Anticancer Agents;208
11.2.1;1. Introduction;208
11.2.1.1;1.1. Overview of Protein Kinase C Isoforms;208
11.2.2;2. Atypical Protein Kinase C Isoforms;209
11.2.2.1;2.1. aPKC Activation Mechanisms;209
11.2.2.2;2.2. aPKC Structure;210
11.2.2.3;2.3. aPKC Function;211
11.2.3;3. Disease Linkage of Atypical PKCs;212
11.2.3.1;3.1. Oncology;212
11.2.3.2;3.2. Metabolic Diseases;213
11.2.3.3;3.3. Other Indications;214
11.2.4;4. Non-ATP-Binding Site Inhibitors;215
11.2.4.1;4.1. PB1 Domain of aPKC (Gold Complexes);215
11.2.4.2;4.2. C-terminal Lobe of the Catalytic Domain of aPKC;215
11.2.4.3;4.3. aPKC Pseudosubstrate Binding Site;216
11.2.4.4;4.4. Allosteric PIF-1 Domain Binding;217
11.2.4.5;4.5. Undefined Binding Modes;217
11.2.5;5. ATP-Binding Site Inhibitors;218
11.2.6;6. Conclusions;221
11.2.7;References;221
12;Section 5: Infectious Diseases;226
12.1;Chapter Fourteen: Advancement of Cell Wall Inhibitors in Mycobacterium tuberculosis;228
12.1.1;1. Introduction;228
12.1.2;2. Cell Wall Inhibitors;230
12.1.2.1;2.1. InhA;230
12.1.2.2;2.2. DprE1;232
12.1.2.3;2.3. MmpL3;233
12.1.2.4;2.4. Peptidoglycan Synthesis;235
12.1.2.5;2.5. Emerging Targets;236
12.1.3;3. Conclusions;236
12.1.4;References;237
12.2;Chapter Fifteen: Nucleosides and Nucleotides for the Treatment of Viral Diseases;240
12.2.1;1. Introduction;240
12.2.2;2. Human Immunodeficiency Virus;241
12.2.3;3. Hepatitis B Virus;247
12.2.4;4. Hepatitis C Virus;250
12.2.5;5. Dengue Virus;259
12.2.6;6. Conclusion;261
12.2.7;References;261
12.3;Chapter Sixteen: Advances in Inhibitors of Penicillin-Binding Proteins and ß-Lactamases as Antibacterial Agents;268
12.3.1;1. Introduction;268
12.3.2;2. PBP Inhibitors;269
12.3.2.1;2.1. ß-Lactam-Based Inhibitors;269
12.3.2.1.1;2.1.1. Cephems: Cephalosporins;270
12.3.2.1.2;2.1.2. Penems: Carbapenems;272
12.3.2.1.3;2.1.3. Monobactams;273
12.3.2.2;2.2. Non-ß-Lactam PBP Inhibitors;274
12.3.2.2.1;2.2.1. Covalent Inhibitors;274
12.3.2.2.2;2.2.2. Noncovalent Inhibitors;275
12.3.3;3. ß-Lactamase Inhibitors;276
12.3.3.1;3.1. Serine ß-Lactamase Inhibitors;276
12.3.3.1.1;3.1.1. DBO-Based BLIs;276
12.3.3.1.2;3.1.2. Boronic Acid-Based BLIs;279
12.3.3.2;3.2. Metallo-ß-Lactamase Inhibitors;279
12.3.3.2.1;3.2.1. Dicarboxylate Inhibitors;280
12.3.3.2.2;3.2.2. Thiolate-Based Inhibitors;281
12.3.3.2.3;3.2.3. Other Small Molecule Inhibitors;281
12.3.4;4. Conclusions and Outlook;282
12.3.5;References;282
13;Section 6: Topics in Biology;286
13.1;Chapter Seventeen: Tumor Microenvironment as Target in Cancer Therapy;288
13.1.1;1. Introduction;288
13.1.2;2. Cancer-Promoting Enzymes and Inhibitors;289
13.1.2.1;2.1. MMPs and Their Inhibitors;289
13.1.2.1.1;2.1.1. Matrix Metalloproteinase-2 and Its Inhibitors;290
13.1.2.1.2;2.1.2. Matrix Metalloproteinase-12 and Its Inhibitors;291
13.1.2.1.3;2.1.3. Matrix Metalloproteinase-13 and Its Inhibitors;292
13.1.2.1.4;2.1.4. Tumor Necrosis Factor--Converting Enzyme and Its Inhibitors;293
13.1.2.2;2.2. Regulation of Microenvironment pH;294
13.1.2.2.1;2.2.1. H+ Pumps and Transporters;294
13.1.2.2.2;2.2.2. Tumor-Associated Carbonic Anhydrases;294
13.1.2.3;2.3. Ectonucleotidases;296
13.1.2.3.1;2.3.1. Autotaxin;296
13.1.2.3.2;2.3.2. CD73;297
13.1.2.3.3;2.3.3. CD39;297
13.1.2.3.4;2.3.4. Miscellaneous;298
13.1.3;3. Carbamoylphosphonates: Inhibitors of Extracellular Zinc-Enzymes;298
13.1.4;4. Conclusions and Outlook;300
13.1.5;Acknowledgments;300
13.1.6;References;301
13.2;Chapter Eighteen: Novel Screening Paradigms for the Identification of Allosteric Modulators and/or Biased Ligands for Cha...;304
13.2.1;1. Introduction;305
13.2.2;2. Allosteric Modulators;306
13.2.2.1;2.1. AM Screening: Challenges;306
13.2.2.2;2.2. AM Screening: Illustrative Examples;307
13.2.2.3;2.3. AM Screening: Novel Approaches;309
13.2.3;3. Biased Ligands;310
13.2.3.1;3.1. BL Identification: Characteristics;310
13.2.3.2;3.2. BL Identification: Illustrative Examples;311
13.2.3.3;3.3. BL Identification: Novel Approaches;313
13.2.4;4. Ab Discovery as Novel AMs/BLs;315
13.2.5;5. Conclusions;317
13.2.6;References;317
13.3;Chapter Nineteen: Mer Receptor Tyrosine Kinase: Therapeutic Opportunities in Oncology, Virology, and Cardiovascular Indic...;320
13.3.1;1. Introduction;321
13.3.2;2. Mer Biological Function and Therapeutic Opportunities;322
13.3.2.1;2.1. Mer´s Role in Macrophages, Natural Killer, and Dendritic Cells;322
13.3.2.2;2.2. Aberrant Expression of Mer in Hematological and Solid Tumors: A Dual Target for Anticancer Effects;323
13.3.2.3;2.3. The Role of TAM Family Kinases in Viral Immune Avoidance;324
13.3.2.4;2.4. Mer´s Role in Coagulation: An Anticoagulation Target with Minimal Bleeding Liabilities;325
13.3.3;3. Small Molecule Mer Inhibitors;325
13.3.3.1;3.1. Current Clinical Agents with TAM Family Activity;326
13.3.3.2;3.2. Novel Mer Inhibitors with Activity in In Vivo Models of Antitumor, Anticoagulation, and Antiviral Indications;326
13.3.4;4. Future Directions and Conclusions;329
13.3.5;References;329
14;Section 7: Topics in Drug Design and Discovery;334
14.1;Chapter Twenty: Disease-Modifying Agents for the Treatment of Cystic Fibrosis;336
14.1.1;1. Introduction;337
14.1.1.1;1.1. Classes of CFTR Mutations;337
14.1.1.2;1.2. Cellular Assays;338
14.1.1.3;1.3. Other Strategies to Correct Airway Surface Liquid Defects;338
14.1.2;2. Treating Class I Defects;339
14.1.2.1;2.1. Ataluren (PTC124, 1);339
14.1.2.2;2.2. NB124 (2);339
14.1.3;3. Treating Class II Defects (Correctors);340
14.1.3.1;3.1. VX-809 (Lumacaftor, 3);340
14.1.3.2;3.2. VX-661 (4);341
14.1.3.3;3.3. FDL169;341
14.1.3.4;3.4. 407882 (5);341
14.1.3.5;3.5. Matrine (6);341
14.1.3.6;3.6. Apoptozole (7);342
14.1.3.7;3.7. Latonduine A (8);342
14.1.3.8;3.8. Kinase Inhibitors;342
14.1.3.9;3.9. Other Correctors;342
14.1.4;4. Treating Class III Defects (Potentiators);343
14.1.4.1;4.1. VX-770 (Ivacaftor, 12);343
14.1.4.2;4.2. RP193;343
14.1.4.3;4.3. GLPG1837;343
14.1.4.4;4.4. Other Potentiators;344
14.1.5;5. Compounds with Dual Activity;344
14.1.5.1;5.1. N6022 (15) and N91115;344
14.1.5.2;5.2. CoPo-22 (16);345
14.1.5.3;5.3. Hyalout4 (17);345
14.1.5.4;5.4. Other Compounds with Dual Activity;345
14.1.6;6. Conclusions;345
14.1.7;References;346
14.2;Chapter Twenty-One: Advancements in Stapled Peptide Drug Discovery and Development;350
14.2.1;1. Introduction;350
14.2.2;2. Beneficial Effects Attributed to the Hydrocarbon Staple;351
14.2.2.1;2.1. Enhancing Pharmacokinetic Properties;352
14.2.2.2;2.2. Generating Cell Permeability;353
14.2.2.3;2.3. Improved Target Affinity and Target Specificity;354
14.2.3;3. Drug Discovery: Preclinical Research;355
14.2.3.1;3.1. BCL-2 Pathway Modulators;355
14.2.3.2;3.2. Wnt Pathway Modulators;357
14.2.3.3;3.3. HIV Inhibitors;358
14.2.4;4. Drug Development and P53 Reactivation;359
14.2.4.1;4.1. From In Vitro to In Vivo Proof of Concept;359
14.2.4.2;4.2. Advantages with SPs over Small Molecules;361
14.2.5;5. Concluding Remarks;361
14.2.6;References;362
14.3;Chapter Twenty-Two: Cytochrome P450 Enzyme Metabolites in Lead Discovery and Development;366
14.3.1;1. Introduction;366
14.3.2;2. Identification of CYP-Modified Natural Products as Drug Leads;367
14.3.2.1;2.1. Antineoplastic Agents;367
14.3.2.2;2.2. Antiprotozoal Agents;368
14.3.2.3;2.3. Antifungal Agents;369
14.3.3;3. Identification of Pharmacologically Active Metabolites of Known Drugs;370
14.3.3.1;3.1. Statin Metabolites;371
14.3.3.2;3.2. Antibiotics;371
14.3.3.3;3.3. Antidepressants;373
14.3.3.4;3.4. Antihistamines;374
14.3.3.5;3.5. Muscarinic Antagonists;374
14.3.3.6;3.6. Antineoplastic Agents;375
14.3.4;4. Future Directions and Conclusions;375
14.3.5;Acknowledgments;376
14.3.6;References;376
15;Section 8: Case Histories and NCEs;380
15.1;Chapter Twenty-Three: Case History: ForxigaTM (Dapagliflozin), a Potent Selective SGLT2 Inhibitor for Treatment of Diabetes;382
15.1.1;1. Introduction;382
15.1.2;2. Renal Recovery of Glucose;383
15.1.3;3. O-Glucoside SGLT2 Inhibitors;385
15.1.4;4. C-Aryl Glucoside SGLT2 Inhibitors;390
15.1.5;5. Synthesis of Dapagliflozin;395
15.1.6;6. Preclinical Profiling Studies with Dapagliflozin;396
15.1.7;7. Clinical Studies with Dapagliflozin;398
15.1.8;8. Conclusion;399
15.1.9;References;400
15.2;Chapter Twenty-Four: Case History: Kalydeco® (VX-770, Ivacaftor), a CFTR Potentiator for the Treatment of Patients with C...;402
15.2.1;1. Introduction;402
15.2.2;2. CFTR as a Drug Discovery Target;404
15.2.3;3. The Discovery of CFTR Potentiators;405
15.2.4;4. Medicinal Chemistry Efforts Culminating in Ivacaftor;405
15.2.4.1;4.1. Hit-to-Lead Efforts;406
15.2.4.2;4.2. Reducing the Planarity of VRT-715;407
15.2.4.3;4.3. Final Compound Selection;409
15.2.5;5. Preclinical Properties of Ivacaftor;410
15.2.6;6. Formulation Development;411
15.2.7;7. Clinical Studies;414
15.2.8;8. Conclusion;415
15.2.9;References;416
15.3;Chapter Twenty-Five: Case History: Xeljanz (Tofacitinib Citrate), a First-in-Class Janus Kinase Inhibitor for the Treatme...;418
15.3.1;1. Introduction;418
15.3.2;2. Rationale for Targeting the JAK Enzymes;420
15.3.3;3. Medicinal Chemistry Efforts Culminating in the Identification of Tofacitinib15;422
15.3.3.1;3.1. Lead Identification: High-Throughput Screening;423
15.3.3.2;3.2. Early Structure-Activity Relationships: Developing a Pharmacophore Model;424
15.3.3.3;3.3. Informing Headgroup Structure: High-Speed Analoging and Natural Products;425
15.3.3.4;3.4. Optimizing Property Space and ADME;427
15.3.4;4. Selectivity and Pharmacology of Tofacitinib;429
15.3.5;5. Preclinical Properties of Tofacitinib;431
15.3.6;6. Clinical Properties of Tofacitinib;432
15.3.7;7. Conclusions;433
15.3.8;Acknowledgments;433
15.3.9;References;433
15.4;Chapter Twenty-Six: New Chemical Entities Entering Phase III Trials in 2013;436
15.4.1;Selection Criteria;436
15.4.2;Facts and Figures;437
15.4.3;References;453
15.5;Chapter Twenty-Seven: To Market, To Market-2013;456
15.5.1;Overview;457
15.5.2;1. Acotiamide (Dyspepsia)11-17;466
15.5.3;2. Ado-Trastuzumab Emtansine (Anticancer)18-22;468
15.5.4;3. Afatinib (Anticancer)23-29;470
15.5.5;4. Canagliflozin (Antidiabetic)30-42;472
15.5.6;5. Cetilistat (Antiobesity)43-52;473
15.5.7;6. Cobicistat (Antiviral, Pharmacokinetic Enhancer)53-59;475
15.5.8;7. Dabrafenib (Anticancer)60-65;477
15.5.9;8. Dimethyl Fumarate (Multiple Sclerosis)66-80;479
15.5.10;9. Dolutegravir (Antiviral)81-91;480
15.5.11;10. Efinaconazole (Antifungal)92-98;482
15.5.12;11. Elvitegravir (Antiviral)99-108;484
15.5.13;12. Ibrutinib (Anticancer)109-114;485
15.5.14;13. Istradefylline (Parkinson´s Disease)115-122;487
15.5.15;14. Lixisenatide (Antidiabetic)123-131;489
15.5.16;15. Macitentan (Antihypertensive)132-138;491
15.5.17;16. Metreleptin (Lipodystrophy)139-150;493
15.5.18;17. Mipomersen (Antihypercholesteremic)151-158;495
15.5.19;18. Obinutuzumab (Anticancer)159-164;497
15.5.20;19. Olodaterol (Chronic Obstructive Pulmonary Disease)165-174;499
15.5.21;20. Ospemifene (Dyspareunia)175-181;501
15.5.22;21. Pomalidomide (Anticancer)182-195;503
15.5.23;22. Riociguat (Pulmonary Hypertension)196-203;505
15.5.24;23. Saroglitazar (Antidiabetic)204-212;507
15.5.25;24. Simeprevir (Antiviral)214-223;508
15.5.26;25. Sofosbuvir (Antiviral)224-235;511
15.5.27;26. Trametinib (Anticancer)236-242;513
15.5.28;27. Vortioxetine (Antidepressant)243-252;515
15.5.29;References;517
16;Keyword Index, Volume 49;528
17;Cumulative Chapter Titles Keyword Index, Volume 1 - 49;538
18;Cumulative NCE Introduction Index, 1983-2013;562
19;Cumulative NCE Introduction Index, 1983-2013 (By Indication);588
20;Color Plate;614

Leseproben

Chapter One A Personal Essay
My Experiences in the Pharmaceutical Industry
John J. Baldwin    Gwynedd Valley, PA, USA I am a chemist, a medicinal chemist, born in Wilmington, Delaware, the cradle of the U.S. chemical industry, the home of DuPont and its postmonopoly offspring, Hercules and Atlas. Wilmington borders on three rivers, the Delaware, the Brandywine, and the Christiana. The fourth connecting side was dominated by the three research centers of DuPont and its spin-offs. Like most budding scientists, I had the obligatory chemistry sets. My dream was to work someday in those beautiful research centers in the Wilmington suburbs, surrounded by parks and golf courses. (Of course there were the other dreams, maybe being a Bishop or riding on horseback into the sunset with imaginary cowboy friends, but that's another story.) When choosing science as a career, it is important to develop a strong foundation in mathematics, languages, biology, chemistry, and physics. It is also important to immerse yourself in a motivating and competitive environment. A strong work ethic is critical. When I attended the University of Delaware as a chemistry major, I carried a full schedule each year while working 24 h a week in the analytical lab at Halby Chemical. My interest in biology was evident in my course selection: biology, physiology, and psychology. My thesis, under John Wriston, focused on the possible fate of one-carbon fragments produced during metabolism. At the University of Delaware, I felt that I had prepared myself to dig deeper into the biological sciences in graduate school. Work hard; study harder. For graduate school, I chose the University of Minnesota and was fortunate to receive a teaching fellowship. I majored in Organic Chemistry and minored in Biochemistry, which was structured within the Medical School. My mentor in synthetic chemistry was Lee Smith, a member of the National Academy of Science and an expert in quinone chemistry, especially as it related to vitamin E and coenzyme Q. My minor in Biochemistry required 2 years of heavy course work. My mentor here was Paul Boyer, the Nobel Prize winner. Working with both of these men was a great experience. My research in synthetic organic chemistry and the courses within the Medical School prepared me well for a future in drug discovery. Work hard; study harder. After saying farewell to graduate school in 1960, I joined the Medicinal Chemistry Department of Merck and Company's West Point, Pennsylvania, laboratory. The company, then known as Merck Sharp & Dohme, had formed through a merger following the discovery at Sharp & Dohme of hydrochlorothiazide, a game changing medication for the treatment of hypertension and, in my thinking, the beginning of modern hypothesis-driven drug discovery. The Merck laboratory in Rahway, New Jersey, focused on antibiotic chemistry, which had evolved from the penicillin program; steroids, which grew out of cortisone synthesis; and vitamins, stemming from their fine chemicals background. The West Point laboratory was devoted to cardiovascular and CNS diseases, antisecretory/antiulcer agents, atherosclerotic disease, and antiviral agents. I became involved in many of the West Point programs, including loop diuretics, xanthine oxidase inhibitors, beta adrenergic blockers, vasodilators, dopamine agents for Parkinson's disease, antivirals, and carbonic anhydrase inhibitors for glaucoma. Learning pharmacology was never ending in the Merck environment. Work hard; study harder. The areas that were especially attractive to me were the mechanistic approach to drug discovery and understanding the biochemistry of disease, using computationally intensive predictive methods and X-ray crystallography of ligand–protein complexes. From this work came Edecrin, Crixivan, Trusopt, Cosopt, and the antiulcer agent famotidine (Pepcid), which I identified in the patent literature and championed through the Merck system. The work, that led to the first topically available carbonic anhydrase inhibitor, dorzolamide (Trusopt), has been described in terms of its design, computational understanding, conformational analysis, and X-ray crystallographic details of the enzyme/ligand structure.1 This integration of disciplines established a powerful approach to drug design that I repeated in the discovery of the HIV protease inhibitors at Merck and the renin inhibitors at Vitae. A compound that created excitement within research but failed to reach the market was the topically penetrating, direct-acting dopamine agonist for Parkinson's disease. The compound was administered via patch and effectively controlled symptoms. However, as sometimes happens, the Research Division could not convince the Clinical/Marketing Organization to continue with clinical trials. In 1993, Merck began to prepare for the twenty-first century and the predicted patent cliff which lay ahead. One step was to decrease staff through a retirement incentive plan. Cut-backs not only pose difficult decisions for management but impose difficult decisions on the people affected as well. Such actions by Merck and other companies marked the disappearance of the lifelong commitment of an employee to a single company and the belief that the commitment of the company to this contract would also be honored. A new era in the company/employee relationship had begun. This new reality became even more apparent over the past decade, and it must be considered by professionals and students alike as they make choices about employment. I adjusted to this apparent evolutionary change by deciding not only to take Merck's offer but to start a new company, Pharmacopeia, which was based on cutting-edge technology not being practiced in Big Pharma. Jack Chabala, also from Merck, and Larry Bock of Avalon Ventures joined me in launching the new company around encoded combinatorial chemistry and high-throughput screening. This technology played a key role in exploiting the genomic revolution and the target-specific approach to drug discovery. Pharmacopeia perfected the synthesis of encoded solid-phase combinational libraries, which allowed the preparation and screening of large compound collections across numerous in vitro assays. These screening collections, built on a common theme, would be followed by smaller libraries focused on the bioactive lead. Within a few years, the approach was adopted by all pharmaceutical companies, and the ability to generate large screening collections became a technology that was required within every drug discovery organization. The only advantage that Pharmacopeia had in selling what had become a commodity was price and its experience in drug discovery. One obvious solution to the price issue was to move compound production to a lower-cost environment. After first looking into a joint venture possibility in China and finding no interest at Pharmacopeia, I, along with one of our founding scientists, Ge Li, and three others decided to finance a new company, WuXi Pharma Tech. This Contract Research Organization grew rapidly and is the largest company in China servicing the research needs of the U.S. and European pharmaceutical industries. With WuXi Pharma Tech successfully listed on the New York Stock Exchange, it was time to start something new. That new endeavor was Concurrent Pharma, later Vitae Pharma, which was based on computational methods from Eugene Shakhnovich's laboratory at Harvard. The method defines in detail a ligand–protein complex that was constructed in silico, fragment by fragment, along the surface of the target. The computational exercise was followed by chemical synthesis of the predicted ligand and appropriate in vitro testing. The predicted complex then could be verified by X-ray crystallography. We found a problem that was ideally suited to test the technology among the aspartic acid proteases, renin and beta-secretase. The approach produced novel, nonpeptidic, and bioavailable inhibitors of both enzymes. A similar approach was used to find inhibitors of 11-beta-hydroxysteroid dehydrogenase, a flexible enzyme that offered an additional challenge. This de novo design strategy holds great promise for the future, especially for the virtual company that lacks the internal architecture of Big Pharma. During this evolutionary period of Vitae Pharma, the drug-discovery capability in China continued to develop such that the time seemed right for a new company not only capable of research support but also of drug discovery, development, toxicology, registration, and human clinical trials, each component present in a virtual organization. So, Bob Nelson of Arch Ventures and I decided to start a new company, Hua Medicine. This China-centric company will move its first drug candidate into human Phase I clinical trials this year, 2013. Looking back to the start of the biotech era, it is clear that start-up companies continue to be a high-risk exercise. Whether the company is large or small, it still takes years and over a billion dollars to discover and develop a New Chemical Entity (NCE). This forces the small biotech firm to be in a constant search for financing and for a viable exit strategy. Recent years have not been easy ones, especially for the major pharmaceutical companies, which faced a slowing rate of discovery, major products going “off patent” into the generic class, higher R&D costs, and longer approval times. To combat this, a range of new survival strategies has been developed and adopted,2,3 including a series of mega-mergers with the resulting cut-back in employment....