Cover
Advisory Board Members
Preface
Part I: General Aspects
1. 1 Trends in Peptide Therapeutics
  1. 1.1 Introduction
  2. 1.2 Peptides in Metabolic Diseases
  3. 1.3 Peptide Antibiotics
  4. 1.4 Peptides in Cancer
  5. 1.5 Peptides in Bone Diseases
  6. 1.6 Peptides in Gastrointestinal Diseases
  7. 1.7 Emerging Trends in Peptide Drug Discovery
  8. 1.8 Summary
  9. Acknowledgment
  10. List of Abbreviations
  11. References
  12. Biographies
2. 2 Physicochemical Parameters of Recently Approved Oral Drugs
  1. 2.1 Introduction
  2. 2.2 FDA‐Approved Drugs 2007–2017
  3. 2.3 Polar Surface Area in bRo5 Territory
  4. References
  5. Biographies
Part II: Drug Class Studies
1. 3 Antibody–Drug Conjugates: Empowering Antibodies for the Fight Against Cancer
  1. 3.1 Introduction
  2. 3.2 First Generation ADCs
  3. 3.3 Second Generation ADCs
  4. 3.4 Toward Next Generation ADCs
  5. 3.5 Summary
  6. List of Abbreviations
  7. References
  8. Biographies
2. 4 Dopamine D₂ Partial Agonists – Discovery, Evolution, and Therapeutic Potential
  1. 4.1 Introduction
  2. 4.2 Dopamine and Dopamine Receptors
  3. 4.3 Schizophrenia and Earlier Antipsychotic Agents
  4. 4.4 Dopamine Partial Agonism
  5. 4.5 D₂ Partial Agonists
  6. 4.6 Marketed D₂ Partial Agonist Antipsychotics
  7. 4.7 Conclusions
  8. List of Abbreviations
  9. References
  10. Biographies
Part III: Case Studies
1. 5 Discovery of Etelcalcetide for the Treatment of Secondary Hyperparathyroidism in Patients with Chronic Kidney Disease
  1. 5.1 Introduction
  2. 5.2 Compound Design and Structure–Activity Relationships
  3. 5.3 Preclinical Studies
  4. 5.4 Mechanism of Action of Etelcalcetide
  5. 5.5 Clinical Studies
  6. 5.6 Summary
  7. Acknowledgments
  8. List of Abbreviations
  9. References
  10. Biographies
2. 6 Development of Lenvatinib Mesylate, an Angiogenesis Inhibitor Targeting VEGF and FGF Receptors
  1. 6.1 Introduction
  2. 6.2 Recent Progress in the Development of Molecular Targeted Anticancer Agents
  3. 6.3 Tumor Angiogenesis
  4. 6.4 Development of Resistance to VEGF‐Targeting Drugs
  5. 6.5 Discovery of Lenvatinib, a Drug Targeting VEGFR and FGFR
  6. 6.6 Inhibition of Kinase Activity by Lenvatinib and Discovery of the Novel Type V Kinase‐Binding Mode
  7. 6.7 Antitumor Effects of Lenvatinib in Human Thyroid Cancer Cell Lines
  8. 6.8 Antitumor Effects of Lenvatinib in Human Renal Cell Cancer Cell Lines and Its Mechanism of Action
  9. 6.9 Conclusions and Perspectives
  10. List of Abbreviations
  11. References
  12. Biographies
3. 7 Ocrelizumab: A New Generation of anti‐CD20 mAb for Treatment of Multiple Sclerosis
  1. 7.1 Introduction: B Cells Play Critical Roles in Immunity
  2. 7.2 Role of B Cells in Autoimmunity
  3. 7.3 CD20‐Targeting Therapeutic Antibodies
  4. 7.4 Rituximab: the First Anti‐CD20 mAb Experience in Autoimmunity
  5. 7.5 Effects of Rituximab on Antibodies and Autoantibodies
  6. 7.6 Rituximab in AAV and Other Autoimmune Disorders
  7. 7.7 Beginnings of Ocrelizumab
  8. 7.8 Multiple Sclerosis
  9. 7.9 Multiple Sclerosis Disease Pathogenesis
  10. 7.10 Rituximab: The First Anti‐CD20 mAb Experience in Multiple Sclerosis
  11. 7.11 Ocrelizumab in Multiple Sclerosis
  12. 7.12 The Conundrum of B Cells in Multiple Sclerosis
  13. 7.13 Final Comments
  14. Acknowledgments
  15. References
  16. Biographies
4. 8 The Story of Rucaparib (Rubraca)
  1. 8.1 Introduction
  2. 8.2 Benzoxazole‐/Benzimidazole‐carboxamides and Quinazolinones
  3. 8.3 The Road to Rucaparib/Rubraca
  4. 8.4 The Emergence of Single‐Agent Therapy
  5. 8.5 Clinical Studies
  6. 8.6 Conclusion
  7. Acknowledgments
  8. References
  9. Biography
5. 9 Discovery and Development of Venetoclax, a Selective Antagonist of BCL‐2
  1. 9.1 Introduction
  2. 9.2 Discovery of Venetoclax – Structure‐Based Design
  3. 9.3 Preclinical Studies
  4. 9.4 Clinical Studies
  5. List of Abbreviations
  6. References
  7. Biographies
Index
End User License Agreement

List of Tables

Chapter 2
1. Table 2.1 Drugs used in the molecular dynamics (MD) analysis.
Chapter 4
1. Table 4.1 Affinity andin vitro functional activity of marketed D₂ parti...
Chapter 5
1. Table 5.1 Properties of Ac‐D‐Cys‐(D‐Arg)_x‐NH₂ peptides.
2. Table 5.2In vitro and in vivo PTH and histamine activity of dCR₆ alanine scan.
3. Table 5.3In vitro and in vivo PTH activity and histamine induction of double‐ala...
4. Table 5.4In vivo activity is dependent on a thiol residue.
5. Table 5.5 Published clinical studies with etelcalcetide.
Chapter 6
1. Table 6.1 Kinetic parameters of inhibitor interaction with VEGFR2. Repr...
2. Table 6.2 Proposed properties of kinase inhibitors [26]. Reprint from [...
Chapter 8
1. Table 8.1 SelectedK _i values for 2‐substituted benzimidazole‐4‐carboxa...
2. Table 8.2 SelectedK _i values for tricyclic benzimidazoles.
3. Table 8.3 SelectedK _i values for tricyclic indoles.
Chapter 9
1. Table 9.1 Acylsulfonamides lacking the P4‐binding “bent‐back” moiety ar...
2. Table 9.2 Binding and functional selectivity.

List of Illustrations

Chapter 1
1. Figure 1.1 Sequences of human, porcine, bovine, and the commercially k...
2. Figure 1.2 Structure of GLP‐1 and marketed analogs.
3. Figure 1.3 Structures of vancomycin (a) and telavancin (b) .
4. Figure 1.4 Structures of (a) LHRH, (b) leuprolide, (c) triptorelin, (d) bu...
5. Figure 1.5 Structures of octreotide (a) and lanreotide (b).
6. Figure 1.6 Structures of (a) human calcitonin, (b) salmon calcitonin, (c) ...
7. Figure 1.7 Structure of teduglutide.
8. Figure 1.8 Structures of (a) guanylin, (b) uroguanylin, (c) linaclotide, a...
9. Figure 1.9 Structures of various CPPs.
Chapter 2
1. Figure 2.1 Distribution of five key molecular descriptors by year and cl...
2. Figure 2.2 Structures of selected drugs.
3. Figure 2.3 Plot of TPSA versus MW for oral drugs approved by the FDA in 20...
4. Figure 2.4 Plot of TPSA versus number of rotatable bonds for oral drugs ap...
5. Figure 2.5 Pie charts show the number and type of Ro5 violations for non...
6. Figure 2.6 Structures of the compounds in Table 2.1.
7. Figure 2.7 Distributions of polar surface area (PSA) and number of intr...
8. Figure 2.8 Distributions of polar surface area (PSA) in molecular dynamics...
9. Figure 2.9 Distributions of (a) solvent‐accessible surface area (SASA) and...
10. Figure 2.10 Most populated clusters of conformations in water (a) and n‐oc...
Chapter 3
1. Figure 3.1 Molecular structure of first generation ADCs comprising N‐Ac γ ...
2. Scheme 3.1 Mechanism of action of Mylotarg^® and Besponsa^® bearin...
3. Figure 3.2 Molecular structure of second generation ADCs and the respectiv...
4. Scheme 3.2 Mechanism of action of Adcetris^® bearing a cleavable linke...
5. Scheme 3.3 Mechanism of action of Kadcyla^® presenting a non‐cleavable...
6. Figure 3.3 Site‐specific ADCs generated by mAb engineering followed by bio...
7. Figure 3.4 Site‐specific ADCs generated by treatment with PNGase F followe...
8. Figure 3.5 Site‐specific ADCs with a DAR of 4 generated by reduction with ...
9. Figure 3.6 SIP(F8)‐SS‐DM1 and IgG(F8)‐SS‐DM1 conjugate, with the formula ...
10. Figure 3.7 Biparatopic mAb conjugated with a tubulysin through a non‐cleav...
11. Figure 3.8 Pyrrolobenzodiazepine dimer‐based ADCs.
12. Figure 3.9 Anthracycline‐based anti‐CD22 ADC.
Chapter 4
1. Figure 4.1 Major dopaminergic pathways.
2. Figure 4.2 Structures of antipsychotics chlorpromazine, clozapine, quetiap...
3. Figure 4.3 Structures of dopamine agonists quinpirole, talipexole, U‐68553...
4. Figure 4.4 Structure of (S)‐(−)‐3‐PPP and homologous cyclic analogs.
5. Figure 4.5 Structures of (6aR)‐apomorphine, (5R),(8R)‐LSD and TDHL.
6. Figure 4.6 Two possible dopamine pharmacophores in LSD.
7. Figure 4.7 Structures of SDZ 208‐911 and SDX 208‐912.
8. Figure 4.8 Structures of early “nonclassical” D₂ partial agonists.
9. Figure 4.9 Representative benzamide D₂ partial agonists.
10. Figure 4.10 D₂ partial agonists and antagonists derived from the benzooxaz...
11. Figure 4.11 Chroman‐derived D₂ partial agonists and bioisosteric analogs....
12. Figure 4.12 COMFA‐derived pharmacophore model of the D₂ binding site.
13. Figure 4.13 Structures of dihydrexidine and traditionally identified D₂ pa...
14. Figure 4.14 Ergoline‐ and aminobenzthiazole‐based D₂ partial agonists ...
15. Figure 4.15 Bivalent D₂ agonists and partial agonists.
16. Figure 4.16 β‐Arrestin‐biased D₂ partial agonists.
17. Figure 4.17 G‐protein‐biased D₂ partial agonists.
18. Figure 4.18 Other G‐protein‐biased D₂ partial agonists.
19. Figure 4.19 Arylpiperazine‐derived D₂ antagonists and partial agonists.
20. Figure 4.20 Representative molecules leading to the discovery of cariprazi...
21. Scheme 4.1 Synthesis of aripiprazole.
22. Figure 4.21 Structure of aripiprazole lauroxil (Aristada^®).
23. Scheme 4.2 Synthesis of brexpiprazole.
24. Scheme 4.3 Original synthesis of cariprazine.
25. Figure 4.22 Relative incidence of side effects seen with “typical” and “at...
Chapter 5
1. Figure 5.1 Effect of D‐peptides with different cationic charge on PTH lowe...
2. Figure 5.2 Acute histamine release following intravenous administration in...
3. Figure 5.3 In vivo PTH‐lowering for alanine‐scan series based on dCR₆ 3....
4. Figure 5.4 In vivo PTH lowering in normal rats for double alanine‐scan se...
5. Figure 5.5 Structure–activity relationships based on double‐Ala substitute...
6. Figure 5.6 Administration of etelcalcetide lowers PTH in rat models of sev...
7. Figure 5.7 Control rat aorta shows normal vascular structural arrangement ...
8. Figure 5.8 Crystal structures of the entire extracellular domain of human ...
9. Figure 5.9 Mean (SD) concentration versus time of total ¹⁴C in blood and p...
Chapter 6
1. Figure 6.1 Angiogenic‐factor‐driven in vitro angiogenesis model. The sTF a...
2. Figure 6.2 Quantitative in vivo angiogenesis assay: dorsal air sac (DAS) a...
3. Figure 6.3 Effect of lenvatinib on survival in a human ovarian cancer SK‐O...
4. Figure 6.4 Scheme of lenvatinib–VEGFR2 interaction. A total of four specif...
Chapter 7
1. Figure 7.1 B cell development and expression of cell surface antigens. (a...
2. Figure 7.2 Negative‐selection checkpoints for central tolerance. Se...
3. Figure 7.3 Structural models of anti‐CD20 antibodies. Surface repre...
Chapter 8
1. Figure 8.1 Structure of nicotinamide adenine dinucleotide (NAD⁺).
2. Scheme 8.1 Mechanism of action of PARP (glutamate carboxylate) on NAD⁺.
3. Scheme 8.2 Formation of aziridinium ion 3 from 2‐chloro‐N‐(2‐chloroethyl)...
4. Figure 8.2 anti‐ and syn‐Conformers of protonated nicotinamide an...
5. Figure 8.3 anti‐ and syn‐Conformers for benzoxazole‐ and benzimidaz...
6. Scheme 8.3 Synthesis of benzimidazole‐4‐carboxamides {reagents: (i) aq. NH
7. Figure 8.4 Crystal structure of 2‐(3‐methoxyphenyl)benzimidazole‐4‐carboxa...
8. Figure 8.5 Evolution of tricyclic PARP‐1 inhibitors (a, 1‐aryl‐8,9‐dihydro...
9. Scheme 8.4 Synthesis of tricyclic benzimidazoles (1‐aryl‐8,9‐dihydro‐2,7,9...
10. Scheme 8.5 Synthesis of tricyclic indoles (5‐aryl‐2,3,4,6‐tetrahydro‐1H‐az...
11. Figure 8.6 Overlay of the structures of 2‐(3‐methoxyphenyl)benzimidazole‐4...
Chapter 9
1. Figure 9.1 (a) Chemical structure of ABT‐737. (b) Chemical structure of n...
2. Figure 9.2 (a) Crystal structure of navitoclax (yellow) in complex with B...
3. Figure 9.3 Modification of the P2‐binding moiety (compound 7) allowed gene...
4. Figure 9.4 (a) The 1.90 Å resolution crystal structure of 7 bound to BCL‐2...

Copyright

Editors

János Fischer

Richter Co., Plc.

Gyömröi ut 19/21

1103 Budapest

Hungary

Christian Klein

Roche Innovation Center Zürich

Cancer Immunotherapy Division

Wagistrasse 10

8952 Schlieren

Switzerland

Wayne E. Childers

Temple University School of Pharmacy

Moulder Ctr. for Drug Discovery Res.

3307 N Broad Street

Philadelphia, PA 19140

United States

Cover

Supported by the international Union of Pure and Applied Chemistry (IUPAC)

Chemistry and Human Health Division

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Preface

The fourth volume of Successful Drug Discovery continues to follow the structure of the previous volumes, consisting of three parts: General Aspects, Drug Class Studies, and Case Studies. The book series focuses on new discoveries of small‐molecule drugs and biologics.

The editors thank the advisory board members: Magid Abou‐Gharbia (Temple University, USA), Jagath R. Junutula (Cellerant Therapeutics, Inc., USA), Kazumi Kondo (Otsuka), John A. Lowe (JL3Pharma LLC, USA), and Gerd Schnorrenberg (Boehringer Ingelheim, Germany), and the following reviewers who helped both the authors and the editors: Jonathan Baell, Gabriele Costantino, György Domány, John M. Beals, Stephen Hauser, Jagath R. Junutula, Béla Kiss, Paul Leeson, Gábor Mező, Tomi Sawyer, Malcolm Stevens, Michael Wagner, Peng Wu. Special thanks are due to Juergen Stohner for his review from the viewpoints of the IUPAC Interdivisional Committee on Terminology, Nomenclature and Symbols (ICTNS).

Part I: General Aspects

John P. Mayer and coworkers give a comprehensive survey on the recent progress in peptide therapeutics. Remarkable achievements in various therapeutic fields and several orally administered peptides are summarized in this chapter.

Andreas Ritzén and coworker investigate the physicochemical parameters of recently approved drugs. A significant fraction of non‐CNS oral drugs violate two or more of the Lipinski parameters.

Part II: Drug Class Studies

Nicolas Joubert and coworkers give an overview on antibody–drug conjugates in cancer‐targeted chemotherapy. Over the last decade, they have been improved by the choice of better drugs, linkers, and mAb targets.

Wayne E. Childers and coworkers evaluate three decades in the discovery of D₂ partial agonist drugs. Progress has been made in treating the negative and cognitive symptoms of schizophrenia.

Part III: Case Studies

Derek Maclean and coworker report on the discovery of etelcalcetide, which affords a suitable therapy for hemodialysis patients with secondary hyperparathyroidism.

Akihiko Tsuruoka and coworkers describe how lenvatinib mesylate was discovered to give a new drug for the treatment of differentiated thyroid cancer.

Andrew C. Chan and coworkers describe the discovery and development of ocrelizumab, which represents a new generation of anti‐CD20 mAb for the treatment of multiple sclerosis.

Bernard T. Golding has prepared a chapter on the discovery and development of rucaparib, a new PARP‐1 inhibitor anticancer drug for the treatment of ovarian cancer. It also represents an example of a good cooperation of academia and industry.

Wayne J. Fairbrother and coworkers describe how venetoclax, a selective antagonist of B cell lymphoma 2 (Bcl‐2), was discovered for the treatment of leukemia.

The editor and authors thank Wiley‐VCH, and personally Dr. Frank Weinreich for the excellent cooperation.

Budapest

Philadelphia

Zurich

8 November 2018

János Fischer

Wayne E. Childers

Christian Klein