Case Studies in Modern Drug Discovery and Development

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Case Studies in Modern Drug Discovery and Development

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  • John Wiley & Sons Inc(2012/06発売)
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  • ポイント 156pt
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  • 製本 Hardcover:ハードカバー版/ページ数 451 p.
  • 言語 ENG
  • 商品コード 9780470601815
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Full Description


Using case studies of successful drug discoveries and launches, this book helps master the necessary knowledge of the drug discovery process. It includes pharmacology, drug metabolism, biology, drug development, and clinical studies. The introduction provides an overview of process, principles, and technologies and each chapter contains case studies that focus on one therapeutic target. It also offers stories from patients who have used the drugs covered as a way to illustrate the impact medicinal chemistry has on real life.

Table of Contents

Preface                                            xv
Contributors xvii
Chapter 1 Introduction: Drug Discovery In 1 (9)
Difficult Times
Malcolm MacCoss
Chapter 2 Discovery And Development Of The 10 (35)
DPP-4 Inhibitor Januvia™
(Sita-Gliptin)
Emma R. Parmee
Ranabir SinhaRoy
Feng Xu
Jeffrey C. Givand
Lawrence A. Rosen
2.1 Introduction 10 (1)
2.2 DPP-4 Inhibition as a Therapy for 10 (10)
Type 2 Diabetes: Identification of Key
Determinants for Efficacy and Safety
2.2.1 Incretin-Based Therapy for T2DM 10 (1)
2.2.2 Biological Rationale: DPP-4 is a 11 (1)
Key Regulator of Incretin Activity
2.2.3 Injectable GLP-1 Mimetics for the 12 (1)
Treatment of T2DM
2.2.4 DPP-4 Inhibition as Oral 12 (1)
Incretin-Based Therapy for T2DM
2.2.5 Investigation of DPP-4 Biology: 13 (2)
Identification of Candidate Substrates
2.2.6 Preclinical Toxicities of 15 (1)
In-Licensed DPP-4 Inhibitors
2.2.7 Correlation of Preclinical 16 (1)
Toxicity with Off-Target Inhibition of
Pro-Specific Dipeptidase Activity
2.2.8 Identification of Pro-Specific 17 (2)
Dipeptidases Differentially Inhibited
by the Probiodrug Compounds
2.2.9 A Highly Selective DPP-4 19 (1)
Inhibitor is Safe and Well Tolerated in
Preclinical Species
2.2.10 A Highly Selective DPP-4 19 (1)
Inhibitor Does Not Inhibit T-Cell
Proliferation in vitro
2.2.11 DPP-4 Inhibitor Selectivity as a 20 (1)
Key Parameter for Drug Development
2.3 Medicinal Chemistry Program 20 (7)
2.3.1 Lead Generation Approaches 20 (1)
2.3.2 Cyclohexyl Glycine α-Amino 20 (2)
Acid Series of DPP-4 Inhibitors
2.3.3 Improving Selectivity of the 22 (1)
α-Amino Acid Series
2.3.4 Identification and Optimization 22 (5)
of the β-Amino Acid Series
2.4 Synthetic and Manufacturing Routes to 27 (6)
Sitagliptin
2.4.1 Medicinal Chemistry Route to 27 (1)
Sitagliptin and Early Modifications
2.4.2 An Asymmetric Hydrogenation 28 (3)
Manufacturing Route to Sitagliptin
2.4.3 A "Greener" Manufacturing Route 31 (2)
to Sitagliptin Employing Biocatalytic
Transamination
2.5 Drug Product Development 33 (3)
2.5.1 Overview 33 (1)
2.5.2 Composition Development 33 (1)
2.5.3 Manufacturing Process Development 33 (3)
2.6 Clinical Studies 36 (3)
2.6.1 Preclinical PD Studies and Early 36 (2)
Clinical Development of Sitagliptin
2.6.2 Summary of Phase II/III Clinical 38 (1)
Trials
2.7 Summary 39 (6)
References 39 (6)
Chapter 3 Olmesartan Medoxomil: An 45 (22)
Angiotensin II Receptor Blocker
Hiroaki Yanagisawa
Hiroyuki Koike
Shin-ichiro Miura
3.1 Background 45 (2)
3.1.1 Introduction 45 (1)
3.1.2 Prototype of Orally Active ARBs 46 (1)
3.2 The Discovery of Olmesartan Medoxomil 47 (6)
(Benicar)
3.2.1 Lead Generation 47 (2)
3.2.2 Lead Optimization 49 (4)
3.3 Characteristics of Olmesartan 53 (3)
3.4 Binding Sites of Omlersartan to the 56 (2)
AT1 Receptor and Its Inverse Agonoist
Activity
3.4.1 Binding Sites of Olmesartan to 56 (1)
the AT1 Receptor
3.4.2 Inverse Agonist Activity of 56 (1)
Olmesartan
3.4.3 Molecular Model of the 57 (1)
Interaction between Olmesartan and the
AT1 Receptor
3.5 Practical Preparation of Olmesartan 58 (1)
Medoxomil
3.6 Preclinical Studies 58 (4)
3.6.1 AT1 Receptor Blocking Action 58 (1)
3.6.2 Inhibition of Ang II-Induced 59 (1)
Vascular Contraction
3.6.3 Inhibition of the Pressor 60 (1)
Response to Ang II
3.6.4 Blood Pressure Lowering Effects 60 (1)
3.6.5 Organ Protection 61 (1)
3.7 Clinical Studies 62 (1)
3.7.1 Antihypertensive Efficacy and 62 (1)
Safety
3.7.2 Organ Protection 63 (1)
3.8 Conclusion 63 (4)
References 64 (3)
Chapter 4 Discovery Of Heterocyclic 67 (21)
Phosphonic Acids As Novel AMP Mimics That
Are Potent And Selective Fructose-1,
6-Bisphosphatase Inhibitors And Elicit
Potent Glucose-Lowering Effects In Diabetic
Animals And Humans
Qun Dang
Mark D. Erion
4.1 Introduction 67 (2)
4.2 The Discovery of MB06322 69 (13)
4.2.1 Research Operation Plan 69 (1)
4.2.2 Discovery of Nonnucleotide AMP 69 (5)
Mimics as FBPase Inhibitors
4.2.3 Discovery of Benzimidazole 74 (3)
Phosphonic Acids as FBPase Inhibitors
4.2.4 Discovery of Thiazole Phosphonic 77 (3)
Acids as Potent and Selective FBPase
Inhibitors
4.2.5 The Discovery of MB06322 Through 80 (2)
Prodrug Strategy
4.3 Pharmacokinetic Studies of MB06322 82 (1)
4.4 Synthetic Routes to MB06322 83 (1)
4.5 Clinical Studies of MB06322 83 (1)
4.5.1 Efficacy Study of Thiazole 12.6 83 (1)
in Rodent Models of T2DM
4.5.2 Phase I/II Clinical Studies 84 (1)
4.6 Summary 84 (4)
References 85 (3)
Chapter 5 Setting The Paradigm Of Targeted 88 (15)
Drugs For The Treatment Of Cancer: Imatinib
And Nilotinib, Therapies For Chronic
Myelogenous Leukemia
Paul W. Manley
Jurg Zimmermann
5.1 Introduction 88 (1)
5.2 Chronic Myelogenous Leukemia (CML) 89 (3)
and Early Treatment of the Disease
5.3 Imatinib: A Treatment for Chronic 92 (2)
Myelogenous Leukemia (CML)
5.4 The Need for New Inhibitorts of 94 (5)
BCR-ABL1 and Development of Nilotinib
5.5 Conclusion 99 (4)
References 100 (3)
Chapter 6 Amrubicin, A Completely Synthetic 103 (24)
9-Aminoanthracycline For Extensive-Disease
Small-Cell Lung Cancer
Mitsuharu Hanada
6.1 Introduction 103 (3)
6.2 The Discovery of Amrubicin: The First 106 (1)
Completely Synthetic Anthracycline
6.3 Toxicological Profile of Amrubicin 107 (3)
6.4 DNA Topoisomerase II Inhibition and 110 (3)
Apoptosis Induction by Amrubicin
6.5 Amrubicin Metabolism: The Discovery 113 (3)
of Amrubicinol
6.5.1 Amrubicinol Functions as an 113 (2)
Active Metabolite of Amrubicin
6.5.2 Tumor-Selective Metabolism of 115 (1)
Amrubicin to Amrubicinol
6.6 Improved Usage of Amrubicin 116 (2)
6.7 Clinical Trials 118 (4)
6.7.1 Clinical Trials of Amrubicin as 118 (3)
First-line Therapy in Patients with
ED-SCLC
6.7.2 Clinical Trials of Amrubicin as 121 (1)
Second-Line Therapy in Patients with
ED-SCLC
6.8 Conclusions 122 (5)
References 123 (4)
Chapter 7 The Discovery Of Dual IGF-1R And 127 (27)
IR Inhibitor FQIT For The Treatment Of
Cancer
Meizhong Jin
Elizabeth Buck
Mark J. Mulvihill
7.1 Biological Rational for Targeting the 127 (1)
IGF-1R/IR Pathway for Anti-Cancer Therapy
7.2 Discovery Of OSI-906 128 (3)
7.2.1 Summary of OSI-906 Discovery 128 (1)
7.2.2 OSI-906 Clinical Aspects 129 (2)
7.3 OSI-906 Back Up Efforts 131 (1)
7.4 The Discovery Of FQIT 131 (9)
7.4.1 Lead Generation Strategy 131 (2)
7.4.2 Small Molecule Dual IGF-1R/IR 133 (1)
Inhibitor Drug Discovery Cascade
7.4.3 Initial Proof-of-Concept Compounds 134 (1)
7.4.4 Synthesis of 5,7-Disubstituted 135 (4)
Imidazo[5,1-f][1,2,4] Triazines
7.4.5 Lead Imidazo[5,1-f][1,2,4] 139 (1)
Triazine IGF-1R/IR Inhibitors and
Emergence of FQIT
7.5 In Vitro Profile of FQIT 140 (4)
7.5.1 Cellular and Antiproliferative 140 (1)
Effects as a Result of IGF-1R and IR
Inhibition
7.5.2 Cellular Potency in the Presence 141 (2)
of Plasma Proteins
7.5.3 In Vitro Metabolism and CYP450 143 (1)
Profile
7.6 Pharmacokinetic Properties of FQIT 144 (2)
7.6.1 Formulation and Salt Study 144 (1)
7.6.2 Pharmacokinetics Following 144 (1)
Intravenous Administration
7.6.3 Pharmacokinetics Following Oral 145 (1)
Administration
7.7 In Vivo Profile of FQIT 146 (2)
7.7.1 In Vivo Pharmacodynamic and PK/PD 146 (1)
Correlation
7.7.2 In Vivo Efficacy 146 (2)
7.8 Safety Assessment and Selectivity 148 (2)
Profile of FQIT
7.8.1 Effects on Blood Glucose and 148 (1)
Insulin Levels
7.8.2 Oral Glucose Tolerance Test 148 (1)
7.8.3 Ames, Rodent, and Nonrodent 149 (1)
Toxicology Studies
7.8.4 Selectivity Profile of FQIT 149 (1)
7.9 Summary 150 (4)
Acknowledgments 151 (1)
References 151 (3)
Chapter 8 Discovery And Development Of 154 (42)
Montelukast (Singulair®)
Robert N. Young
8.1 Introduction 154 (4)
8.2 Drug Development Strategies 158 (1)
8.3 LTD4 Antagonist Program 159 (1)
8.3.1 Lead Generation and Optimization 159 (1)
8.3.2 In Vitro and In Vivo Assays 159 (1)
8.4 The Discovery of Montelukast 160 (14)
(Singulair®)
8.4.1 First-Generation Antagonists 160 (3)
(Figure 8.3)
8.4.2 Discovery of MK-571 163 (5)
8.4.3 Discovery of MK-0679 (29) 168 (3)
8.4.4 Discovery of Montelukast 171 (3)
(L-706,631, MK-0476, Singulair®)
8.5 Synthesis of Montelukast 174 (5)
8.5.1 Medicinal Chemistry Synthesis 174 (2)
8.5.2 Process Chemistry Synthesis [104, 176 (3)
105] (Schemes 8.5 and 8.6)
8.6 ADME Studies with MK-0476 179 (1)
(Montelukast)
8.7 Safety Assessment of Montelukast 180 (1)
8.8 Clinical Development of Montelukast 180 (5)
8.8.1 Human Pharmacokinetics, Safety, 180 (1)
and Tolerability
8.8.2 Human Pharmacology 181 (1)
8.8.3 Phase 2 Studies in Asthma 182 (1)
8.8.4 Phase 3 Studies in Asthma 182 (3)
8.8.5 Effects of Montelukast on 185 (1)
Inflammation
8.8.6 Montelukast and Allergic Rhinitis 185 (1)
8.9 Summary 185 (2)
8.9.1 Impact on Society 185 (1)
8.9.2 Lessons Learned 186 (1)
8.10 Personal Impact 187 (9)
References 188 (8)
Chapter 9 Discovery And Development Of 196 (31)
Maraviroc, A CCR5 Antagonist For The
Treatment Of HIV Infection
Patrick Dorr
Blanda Stammen
Elna van der Ryst
9.1 Background and Rationale 196 (3)
9.2 The Discovery of Maraviroc 199 (2)
9.2.1 HTS and Biological Screening to 199 (1)
Guide Medicinal Chemistry
9.2.2 Hit Optimization 200 (1)
9.2.3 Overcoming Binding to hERG 201 (1)
9.3 Preclinical Studies 201 (4)
9.3.1 Metabolism and Pharmacokinetic 201 (1)
Characteristics of Maraviroc
9.3.2 Maraviroc Preclinical Pharmacology 202 (1)
9.3.3 Preclinical Investigations into 202 (2)
HIV Resistance
9.3.4 Binding of Maraviroc to CCR5 204 (1)
9.4 The Synthesis of Maraviroc 205 (1)
9.5 Nonclinical Safety and Toxicity 206 (1)
Studies
9.5.1 Safety Pharmacology 206 (1)
9.5.2 Immuno- and Mechanistic Toxicity 206 (1)
9.6 Clinical Development of Maraviroc 207 (7)
9.6.1 Phase 1 Studies 207 (2)
9.6.2 Phase 2a Studies 209 (1)
9.6.3 Phase 2b/3 Studies 210 (3)
9.6.4 Development of Resistance to CCR5 213 (1)
Antagonists In Vivo
9.7 Summary, Future Directions, and 214 (13)
Challenges
Acknowledgments 217 (1)
References 217 (10)
Chapter 10 Discovery Of Antimalarial Drug 227 (30)
Artemisinin And Beyond
Weiwei Mao
Yu Zhang
Ao Zhang
10.1 Introduction: Natural Products in 227 (1)
Drug Discovery
10.2 Natural Product Drug Discovery in 227 (1)
China
10.3 Discovery of Artemisinin: 228 (4)
Background, Structural Elucidation and
Pharmacological Evaluation
10.3.1 Background and Biological 228 (1)
Rationale
10.3.2 The Discovery of Artemisinin 229 (2)
through Nontraditional Drug Discovery
Process
10.3.3 Structural Determination of 231 (1)
Artemisinin
10.3.4 Pharmacological Evaluation and 231 (1)
Clinical Trial Summary of Artemisinin
10.4 The Synthesis of Artemisinin 232 (6)
10.4.1 Synthesis of Artemisinin using 233 (3)
Photooxidation of Cyclic or Acyclic
Enol Ether as the Key Step
10.4.2 Synthesis of Artemisinin by 236 (1)
Photooxidation of Dihydroarteannuic Acid
10.4.3 Synthesis of Artemisinin by 236 (2)
Ozonolysis of a Vinylsilane Intermediate
10.5 SAR Studies of Structural 238 (10)
Derivatives of Artemisinin: The Discovery
of Artemether
10.5.1 C-10-Derived Artemisinin Analogs 240 (5)
10.5.2 C-9 and C-9,10 Double 245 (1)
Substituted Analogs
10.5.3 C-3 Substituted Analogs 246 (1)
10.5.4 C-6 or C-7 Substituted 246 (1)
Derivatives
10.5.5 C-11-Substituted Analogs 247 (1)
10.6 Development of Artemether 248 (2)
10.6.1 Profile and Synthesis of 248 (1)
Artemether
10.6.2 Clinical Studies Aspects of 249 (1)
Artemether
10.7 Conclusion and Perspective 250 (7)
Acknowledgment 250 (1)
References 251 (6)
Chapter 11 Discovery And Process 257 (39)
Development Of MK-4965, A Potent
Nonnucleoside Reverse Transcriptase
Inhibitor
Yong-Li Zhong
Thomas J. Tucker
Jingjun Yin
11.1 Introduction 257 (3)
11.2 The Discovery of MK-4965 260 (6)
11.2.1 Background Information 260 (2)
11.2.2 SAR Studies Leading to the 262 (4)
Discovery of MK-4965
11.3 Preclinical and Clinical Studies of 266 (1)
MK-4965 (19)
11.4 Summary of Back-Up SAR Studies of 266 (1)
MK-4965 Series
11.5 Process Development of MK-4965 (19) 267 (23)
11.5.1 Medicinal Chemistry Route 267 (2)
11.5.2 Process Development 269 (21)
11.6 Conclusion 290 (6)
11.6.1 Lessons Learned from the 290 (1)
Medicinal Chemistry Effort of MK-4965
Discovery
11.6.2 Summary and Lessons Learned from 291 (1)
the Process Development of MK-4965
Acknowledgments 291 (1)
References 291 (5)
Chapter 12 Discovery Of Boceprevir And 296 (40)
Narlaprevir: The First And Second
Generation Of HCV NS3 Protease Inhibitors
Kevin X. Chen
F. George Njoroge
12.1 Introduction 296 (2)
12.2 HCV NS3 Protease Inhibitors 298 (4)
12.3 Research Operation Plan and 302 (1)
Biological Assays
12.3.1 Research Operation Plan 302 (1)
12.3.2 Enzyme Assay 302 (1)
12.3.3 Replicon Assay 302 (1)
12.3.4 Measure of Selectivity 303 (1)
12.4 Discovery of Boceprevir 303 (14)
12.4.1 Initial Lead Generation Through 303 (1)
Structure-Based Drug Design
12.4.2 SAR Studies Focusing on 304 (3)
Truncation, Depeptization, and
Macrocyclisation
12.4.3 Individual Amino Acid Residue 307 (8)
Modifications
12.4.4 Correlations Between P1, P3, and 315 (2)
P3 Capping: The Identification of
Boceprevir
12.5 Profile of Boceprevir 317 (2)
12.5.1 In Vitro Characterization of 317 (1)
Boceprevir
12.5.2 Pharmacokinetics of Boceprevir 317 (1)
12.5.3 The Interaction of Boceprevir 318 (1)
with NS3 Protease
12.6 Clinical Development and Approval of 319 (1)
Boceprevir
12.7 Synthesis of Boceprevir 319 (3)
12.8 Discovery of Narlaprevir 322 (7)
12.8.1 Criteria for the Back-up Program 322 (1)
of Boceprevir
12.8.2 SAR Studies 322 (4)
12.8.3 Profile of Narlaprevir 326 (1)
12.8.4 Clinical Development Aspects of 327 (1)
Narlaprevir
12.8.5 Synthesis of Narlaprevir 327 (2)
12.9 Summary 329 (7)
References 330 (6)
Chapter 13 The Discovery Of Samsca® 336 (24)
(Tolvaptan): The First Oral Nonpeptide
Vasopressin Receptor Antagonist
Kazumi Kondo
Yoshitaka Yamamura
13.1 Background Information about the 336 (1)
Disease
13.2 Biological Rational 337 (1)
13.3 Lead Generation Strategies: The 338 (9)
Discovery of Mozavaptan
13.4 Lead Optimization: From Mozavaptan 347 (3)
to Tolvaptan
13.5 Pharmacological Profiles of Tolvaptan 350 (3)
13.5.1 Antagonistic Affinities of 350 (2)
Tolvaptan for AVP Receptors
13.5.2 Aquaretic Effect Following a 352 (1)
Single Dose in Conscious Rats
13.6 Drug Development 353 (3)
13.6.1 Synthetic Route of Discovery and 353 (1)
Commercial Synthesis [10a]
13.6.2 Nonclinical Toxicology 353 (2)
13.6.3 Clinical Studies 355 (1)
13.7 Summary Focusing on Lessons Learned 356 (4)
Acknowledgments 357 (1)
References 357 (3)
Chapter 14 Silodosin (Urief®, 360 (32)
Rapaflo®, Thrupas®, Urorec®,
Silodix™): A Selective α1A
Adrenoceptor Antagonist For The Treatment
Of Benign Prostatic Hyperplasia
Masaki Yoshida
Imao Mikoshiba
Katsuyoshi Akiyama
Junzo Kudoh
14.1 Background Information 360 (2)
14.1.1 Benign Prostatic Hyperplasia 360 (1)
14.1.2 α1-Adrenergic Receptors 361 (1)
14.2 The Discovery of Silodosin 362 (7)
14.2.1 Medicinal Chemistry 362 (1)
14.2.2 The Synthesis of Silodosin 363 (2)
(Discovery Route)
14.2.3 Receptor Binding Studies 365 (4)
14.3 Pharmacology of Silodosin 369 (4)
14.3.1 Action Against 369 (2)
Noradrenalin-Induced Contraction of
Lower Urinary Tract Tissue
14.3.2 Actions Against 371 (1)
Phenylephrine-Induced Increase in
Intraurethral Pressure and Blood
Pressure
14.3.3 Actions Against Intraurethral 372 (1)
Pressure Increased by Stimulating
Hypogastric Nerve and Blood Pressure in
Dogs with Benign Prostatic Hyperplasia
14.3.4 Safety Pharmacology 373 (1)
14.4 Metabolism of Silodosin 373 (3)
14.5 Pharmacokinetics of Silodosin 376 (3)
14.5.1 Absorption 376 (1)
14.5.2 Organ Distribution 377 (1)
14.5.3 Excretion 378 (1)
14.6 Toxicology of Silodosin 379 (3)
14.7 Clinical Trials 382 (6)
14.7.1 Phase I Studies 382 (1)
14.7.2 Phase III Randomized, 383 (2)
Placebo-Controlled, Double-Blind Study
14.7.3 Long-Term Administration Study 385 (3)
14.8 Summary: Key Lessons Learned 388 (4)
References 389 (3)
Chapter 15 Raloxifene: A Selective Estrogen 392 (25)
Receptor Modulator (Serm)
Jeffrey A. Dodge
Henry U. Bryant
15.1 Introduction: SERMs 392 (2)
15.2 The Benzothiophene Scaffold: A New 394 (1)
Class of SERMs
15.3 Assays for Biological Evaluation of 394 (1)
Tissue Selectivity
15.4 Benzothiophene Structure Activity 395 (6)
15.5 The Synthesis of Raloxifene 401 (1)
15.6 SERM Mechanism 402 (3)
15.7 Raloxifene Pharmacology 405 (6)
15.7.1 Skeletal System 405 (2)
15.7.2 Reproductive System---Uterus 407 (1)
15.7.3 Reproductive System---Mammary 408 (2)
15.7.4 General Safety Profile and Other 410 (1)
Pharmacological Considerations
15.8 Summary 411 (6)
References 411 (6)
Appendix I Small Molecule Drug Discovery And 417 (2)
Development Paradigm
Appendix II Glossary 419 (13)
Appendix III Abbreviations 432 (11)
Index 443