Innovative Drug Synthesis E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Serie: Wiley Series on Drug Synthesis
- Sprache: Englisch
This book covers all aspects of the medicinal chemistry of the latest drugs, and the cutting-edge science associated with them. Following the editors' 3 successful drug synthesis books, this provides expert analysis of the pros and cons of different synthetic routes and demystifies the process of modern drug discovery for practitioners and researchers. * Summarizes for each drug: respective disease area, important properties and SAR (structure-activity relationship), and chemical synthesis routes / options * Includes case studies in each chapter * Illustrates how chemistry, biology, pharmacokinetics, and a host of disciplines come together to produce successful medicines * Explains the advantages of process synthesis versus the synthetic route for drug discovery
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Table of Contents
Cover
Title Page
Copyright
Preface
Contributors
Part I: Infectious Diseases
Chapter 1: Entecavir (Baraclude): A Carbocyclic Nucleoside for the Treatment for Chronic Hepatitis B
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 References
Chapter 2: Telaprevir (Incivek) and Boceprevir (Victrelis): NS3/4A Inhibitors for Treatment for Hepatitis C Virus (HCV)
1 Background
2 Pharmacology
3 Structure-activity relationship (SAR)
4. PK and Drug Metabolism
5 Efficacy and Safety
6 Synthesis
7 Conclusion
8 References
Chapter 3: Daclatasvir (Daklinza): The First-in-Class HCV NS5A Replication Complex Inhibitor
1 Background
2 Discovery Medicinal Chemistry
3 Mode of Action
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 References
Chapter 4: Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 Summary
Acknowledgements
8 References
Chapter 5: Bedaquiline (Situro): A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6
Syntheses
7 References
Part II: Cancer
Chapter 6: Enzalutamide (Xtandi): An Androgen Receptor Antagonist for Late-Stage Prostate Cancer
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 Compounds in Development
8 References
Chapter 7: Crizotinib (Xalkori): The First-in-Class ALK/ROS Inhibitor for Non-small Cell Lung Cancer
1 Background: Non-small Cell Lung Cancer (NSCLC) Treatment
2 Discovery Medicinal Chemistry Effort: SAR and Lead Optimization of Compound 2 as a c-Met Inhibitor
3 ALK and ROS in Non-small Cell Lung Cancer (NSCLC) Treatment
4 Preclinical Model Tumor Growth Inhibition Efficacy and Pharmacology
5 Human Clinical Trials
6 Introduction to the Synthesis and Limitations of the Discovery Route to Crizotinib Analogs
7 Process Chemistry: Initial Improvements
8 Process Chemistry: Enabling Route to Crizotinib
9 Development of the Commercial Process
10 Commercial Synthesis of Crizotinib
Acknowledgements
11 References
Chapter 8: Ibrutinib (Imbruvica): The First-in-Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 Referesnces
Chapter 9: Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer
1 Background
2 Pharmacology
3 Discovery Program
4 Preclinical Profile of Palbociclib
5 Clinical Profile of Palbociclib
6 Early Process Development for Palbociclib
7 Commercial Process for Preparation of Palbociclib
Acknowledgments
8 References
Part III: Cardiovascular Diseases
Chapter 10: Ticagrelor (Brilinta) and Dabigatran Etexilate (Pradaxa): P2Y
12
Platelet Inhibitors as Anticoagulants
1 Introduction
2 Dabigatran Etexilate
3 Ticagrelor
4 The Future
5 References
Part IV: CNS Drugs
Chapter 11: Suvorexant (Belsomra), The First-in-Class Orexin Antagonist for Insomnia
1 Background
2 Pharmacology
3 Pharmacokinetics and Drug Metabolism
4 Efficacy and Safety
5 Structure–Activity Relationship (SAR)
6 Synthesis
6.3 Alternative Synthesis
7 References
Chapter 12: Lorcaserin (Belviq): Serotonin 2C Receptor Agonist for the Treatment of Obesity
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 References
Chapter 13: Fingolimod (Gilenya): The First Oral Treatment for Multiple Sclerosis
1 Background
2 Structure–Activity Relationship (SAR)
3 Pharmacology
4 Human Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 Summary
8 References
Chapter 14: Perampanel (Fycompa): AMPA Receptor Antagonist for the Treatment of Seizure
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 References
Part V: Anti-Inflammatory Drugs
Chapter 15: Tofacitinib (Xeljanz): The First-in-Class JAK Inhibitor for the Treatment of Rheumatoid Arthritis
1 Background
2 Structure–Activity Relationships (SAR)
3 Safety, Pharmacology, and Pharmacokinetics
4 Syntheses
5 Development of the Commercial Manufacturing Process
Acknowledgments
6 References
Part VI: Miscellaneous Drugs
Chapter 16: Ivacaftor (Kalydeco): A CFTR Potentiator for the Treatment of Cystic Fibrosis
1 Background
2 Pharmacology
3 Structure–Activity Relationship (SAR)
15,16
4 Pharmacokinetics and Drug Metabolism
17–20
5 Efficacy and Safety
6 Syntheses
7 References
Chapter 17: Febuxostat (Uloric): A Xanthine Oxidase Inhibitor for the Treatment of Gout
1 Background
2 Pharmacology
3 Structure-Activity Relationship (SAR)
4 Pharmacokinetics and Drug Metabolism
5 Efficacy and Safety
6 Syntheses
7 Drug in Development: Lesinurad Sodium
39
8 References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Infectious Diseases
Begin Reading
List of Illustrations
Chapter 2: Telaprevir (Incivek) and Boceprevir (Victrelis): NS3/4A Inhibitors for Treatment for Hepatitis C Virus (HCV)
Figure 1 Boceprevir SAR.
Figure 2 Telaprevir SAR.
Scheme 1 Retrosynthetic analysis of boceprevir.
Scheme 2 Medicinal chemistry synthesis of P1 fragment of boceprevir.
Scheme 3 Medicinal chemistry synthesis of P2 fragment of boceprevir.
Scheme 4 Medicinal chemistry synthesis: Fragment coupling and completion of boceprevir.
Scheme 5 First-generation process synthesis of P2 fragment 24.
Scheme 6 Second-generation process synthesis of P2 intermediate 24.
Scheme 7 Enzymatic manufacturing process for intermediate 24.
Scheme 8 Telaprevir synthetic strategy.
Scheme 9 Discovery synthesis of P1 fragment of telaprevir.
Scheme 10 Discovery synthesis of P2 domain of telaprevir.
Scheme 11 Discovery synthesis: Assembly of telaprevir.
Scheme 12 Process synthesis of P1 fragment of telaprevir.
Scheme 13 Process synthesis of P2 domain of telaprevir.
Scheme 14 Process synthesis: completion of telaprevir synthesis.
Scheme 15 Three-component coupling approach to telaprevir.
Chapter 3: Daclatasvir (Daklinza): The First-in-Class HCV NS5A Replication Complex Inhibitor
Scheme 1 First synthesis of DCV.
Scheme 2 Mechanism of imidazole formation.
Scheme 3 Retrosynthetic analysis, Path A and Path B.
Scheme 4 Retrosynthetic analysis, Path C and Path D.
Scheme 5 First generation route.
Scheme 6 Commercial route.
Chapter 4: Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor
Figure 1 Early HCV NS5B nucleoside polymerase inhibitors.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Chapter 5: Bedaquiline (Situro): A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis
Figure 1 Binding interaction of subunit c group Glu-61 and subunit a group Arg-186 in ATP synthase with bedaquiline.
18
Chapter 6: Enzalutamide (Xtandi): An Androgen Receptor Antagonist for Late-Stage Prostate Cancer
Figure 1 Non-steroidal androgen receptor antagonists.
Figure 2 Early drug candidates and the native ligand for androgen receptor.
Figure 3 Compounds with a high binding affinity to the androgen receptor.
Figure 4 Compounds that failed to show any activities
in vitro
assays.
Figure 5 Enzalutamide and its major metabolite.
Figure 6 Enzalutamide is approved to treat docetaxel-refractory metastatic castration-resistant prostate cancer.
Scheme 1 First discovery route to diversify the thiohydantoin structures.
Scheme 2 Second discovery route to diversify the thiohydantoin structures.
Scheme 3 The process for the synthesis of enzalutamide.
Scheme 4 An alternative route for the synthesis of enzalutamide.
Chapter 7: Crizotinib (Xalkori): The First-in-Class ALK/ROS Inhibitor for Non-small Cell Lung Cancer
Figure 1 Docked compound
2
/unphosphorylated c-Met KD cocrystal structure.
Figure 2 Compound
6
/unphosphorylated c-Met KD cocrystal structure
:
the
R
-Me group of
6
occupied a small hydrophobic group highlighted by the surface.
Figure 3 Overlap of c-Met, ALK, and ROS cocrystal structures with crizotinib. c-Met (PDB 2wgi); ALK (PDB 2xp2); ROS (PDB 3zbf).
Figure 4 Summary of the enabling route.
Figure 5 Structure of modified Naud's catalyst.
Figure 6 Coupling approaches to the key intermediate.
Figure 7 Catalytic cycle for the Cu-mediated coupling.
Figure 8 Proposed commercial route to crizotinib.
Figure 9 Work-up of boronate coupling partner.
Figure 10 Summary of the commercial route to crizotinib.
Scheme 1 Discovery route to crizotinib analogs.
Scheme 2 PLE-mediated resolution to access the enantiopure alcohols.
Scheme 3 Synthesis of bromide intermediate.
Scheme 4 Synthesis of the boronate ester.
Scheme 5 Suzuki coupling.
Scheme 6 Deprotection and isolation of crizotinib.
Scheme 7 Chemoselective reduction of the acetophenone.
Scheme 8 Initial ketoreductase route to the enantiopure alcohol.
Scheme 9 Optimized Mitsunobu reaction with product isolation.
Scheme 10 Nitro group hydrogenation.
Scheme 11 Chemoselective bromination to access the key intermediate.
Scheme 12 Optimized formation of the boronate ester.
Scheme 13 Modified Suzuki coupling/work-up and isolation.
Scheme 14 Deprotection and isolation of crizotinib in enabling route.
Scheme 15 Second-generation ketoreductase route to the enantiopure alcohol.
Scheme 16 Model studies on metal-mediated couplings.
Scheme 17 Activation-displacement approach to the key intermediate.
Scheme 18 Synthesis of 2-amino-3-hydroxy-5-bromopyridine.
Scheme 19 Synthesis of new pyrazole intermediate.
Scheme 20 Optimized activation and displacement chemistry.
Scheme 21 Formation of the boronate coupling partner.
Scheme 22 Optimized final Suzuki coupling.
Chapter 9: Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Scheme 8
Scheme 9
Scheme 10
Scheme 11
Scheme 12
Scheme 13
Scheme 14
Scheme 15
Scheme 16
Scheme 17
Scheme 18
Scheme 19
Scheme 20
Chapter 10: Ticagrelor (Brilinta) and Dabigatran Etexilate (Pradaxa): P2Y
12
Platelet Inhibitors as Anticoagulants
Scheme 1 Medicinal chemistry from NAPAP to dabigatran.
Scheme 2 Medicinal chemistry for the prodrug of dabigatran.
Scheme 3 Four fragments of dabigatran etexilate.
Scheme 4 The synthetic route of dabigatran etexilate.
Scheme 5 The alternative synthesis route of dabigatran etexilate.
Scheme 6 The improved synthesis route of dabigatran etexilate.
Scheme 7 The novel synthesis route of dabigatran etexilate.
Scheme 8 Medicinal chemistry from ATP to ticagrelor
Scheme 9 Three fragments of ticagrelor.
Scheme 10 The synthetic route of ticagrelor fragment
27
Scheme 11 The another synthetic route of ticagrelor fragment
27
Scheme 12 The synthesis route of ticagrelor fragment
28
.
Scheme 13 The alternative synthesis route of ticagrelor fragment
28
.
Scheme 14 The synthesis route of ticagrelor fragment
29
.
Scheme 15 The synthetic route of ticagrelor fragment
29
by using (
S
)-diphenylprolinol as chiral auxiliary reagent.
Scheme 16 The convergent strategy of synthesizing ticagrelor.
Scheme 17 One-pot strategy of synthesizing ticagrelor.
Scheme 18 The synthetic route of ticagrelor via new intermediates.
Chapter 12: Lorcaserin (Belviq): Serotonin 2C Receptor Agonist for the Treatment of Obesity
Scheme 1 Discovery synthesis via the intramolecular Heck route.
Scheme 2 Lorcaserin synthesis via the Friedel–Crafts reactions.
Scheme 3 Lorcaserin process synthesis via Friedel–Crafts reactions.
Chapter 13: Fingolimod (Gilenya): The First Oral Treatment for Multiple Sclerosis
Figure 1 Identification of ISP-1as a potent immunosuppressant led to SAR efforts to identify fingolimod, the first oral treatment for multiple sclerosis.
Figure 2 SAR attributes of ISP-1 leading to the discovery of fingolimod.
Figure 3 Similar to sphingosine, fingolimod is a prodrug for an active phosphorylated metabolite.
Figure 4 Human metabolic profile generated using radiolabeled fingolimod.
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Scheme 5
Chapter 14: Perampanel (Fycompa): AMPA Receptor Antagonist for the Treatment of Seizure
Figure 1 Examples of AMPA receptor antagonists.
Chapter 16: Ivacaftor (Kalydeco): A CFTR Potentiator for the Treatment of Cystic Fibrosis
Figure 1 Model of CF lung disease
2
List of Tables
Chapter 1: Entecavir (Baraclude): A Carbocyclic Nucleoside for the Treatment for Chronic Hepatitis B
Table 1 Potency of various nucleoside analogs for HBV inhibition based on the EC
50
for inhibition of HBV replicase in HepG2.2.15 cell line.
13
Table 2 Activity of nucleoside analogs against HBV in HepG2.2.15 cells.
Chapter 2: Telaprevir (Incivek) and Boceprevir (Victrelis): NS3/4A Inhibitors for Treatment for Hepatitis C Virus (HCV)
Table 1 Preclinical pharmacokinetic profiling of boceprevir.
Table 2 Preclinical pharmacokinetic profiling of telaprevir.
Table 1 Green chemistry metrics for scale-up of
24
.
Chapter 4: Sofosbuvir (Sovaldi): The First-in-Class HCV NS5B Nucleotide Polymerase Inhibitor
Table 1 HCV replicon activity of 16 phosphoramidate prodrugs with simultaneous carboxylate and phosphate ester modification.
Table 2 PK parameters of 2′-deoxy-2′-fluoro-2′-
C
-methyluridine triphosphate (
11
) in rat liver after an oral dose of 50 mg/kg for seven phosphoramidate prodrugs.
Table 3 Dog and monkey plasma and liver PK profile after oral dose of 50 mg/kg for three phosphoramidate prodrugs of 2′-deoxy-2′-fluoro-2′-
C
-methyluridine.
Chapter 5: Bedaquiline (Situro): A Diarylquinoline that Blocks Tuberculosis ATP Synthase for the Treatment of Multi-Drug Resistant Tuberculosis
Table 1 CYP450-based drug interactions with bedaquiline (
1
)
21
Chapter 6: Enzalutamide (Xtandi): An Androgen Receptor Antagonist for Late-Stage Prostate Cancer
Table 1 Structure-activity relationship studies.
Chapter 7: Crizotinib (Xalkori): The First-in-Class ALK/ROS Inhibitor for Non-small Cell Lung Cancer
Table 1 Structure-activity relationship of 2-aminopyridine analogs.
Table 2 Kinase selectivity assays and cell-based ELISA IC50s for antiphosphorylation of kinases.
Table 3 Preclinical xenograph model efficacy for crizotinib.
Chapter 8: Ibrutinib (Imbruvica): The First-in-Class Btk Inhibitor for Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, and Waldenstrom's Macroglobulinemia
Table 1 Compounds with various types of Michael acceptors are potent inhibitors against Btk.
8
Chapter 9: Palbociclib (Ibrance): The First-in-Class CDK4/6 Inhibitor for Breast Cancer
Table 1 Compounds illustrating the general effect of nitrogen replacement in the side chain on selectivity for inhibition of CDK4.
23
Chapter 11: Suvorexant (Belsomra), The First-in-Class Orexin Antagonist for Insomnia
Table 1 DORAs advanced to clinical trials.
Table 3 Pharmacokinetic profile of suvorexant.
Table 4 PK evaluation of compound
12
Chapter 12: Lorcaserin (Belviq): Serotonin 2C Receptor Agonist for the Treatment of Obesity
Table 1 Comparison between lorcaserin and placebo effects on a randomized selection of patients.
*
Table 2 List of some of the substituents added, specifically identifying their position in the benzyl group and whether it was a mixture of both isomers and either the
R
or
S
conformation.
*
Table 3 The percentage of 2C receptor inhibition as observed by the acute food intake of rats 2 h after the dose was administered.
*
Table 4 Summary of the pharmacokinetics of lorcaserin (1–3 mg/kg SC) in SD rats.
16
Table 5 Pharmacokinetic parameters of lorcaserin in male Sprague-Dawley rats.
9 *
Chapter 13: Fingolimod (Gilenya): The First Oral Treatment for Multiple Sclerosis
Table 1 Trials and outcomes of treating MS patients with fingolimod.
Chapter 14: Perampanel (Fycompa): AMPA Receptor Antagonist for the Treatment of Seizure
Table 1 Effects of perampanel on induced seizures.
Table 2 SAR of the 1,3,5-triaryl pyridone series.
Table 3 Phase 3 clinical results.
Chapter 15: Tofacitinib (Xeljanz): The First-in-Class JAK Inhibitor for the Treatment of Rheumatoid Arthritis
Table 1 Enzyme and cellular potency for select JAK inhibitors along with half-lives for human liver microsome (HLM) incubations.
Chapter 17: Febuxostat (Uloric): A Xanthine Oxidase Inhibitor for the Treatment of Gout
Table 1 Comparative inhibitory constants (IC
50
) against xanthine oxidase
Table 2 Comparative inhibitory constants (IC
50
) against xanthine oxidase.
11, 24
Table 3 Phase II clinical trial of febuxostat for gout.
33
Table 4 Screening of palladium-catalyzed heteroaryl Heck reaction.
38
Innovative Drug Synthesis
Edited by:
Jie Jack Li
University of San Francisco
and
Douglas S. Johnson
Pfizer Worldwide Research and Development
Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved
Published by John Wiley & Sons, Inc., Hoboken, New Jersey
Published simultaneously in Canada
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Library of Congress Cataloging-in-Publication Data.
Innovative drug synthesis / edited by Jie Jack Li, Douglas S. Johnson.
pages cm -- (Drug synthesis series)
Includes bibliographical references and index.
ISBN 978-1-118-82005-6 (cloth)
1. Drugs--Design. 2. Pharmaceutical chemistry. I. Li, Jie Jack, editor. II. Johnson, Douglas S. (Douglas Scott), 1968- editor.
RS420.I55 2015
615.1′9--dc23
2015022461
Cover image courtesy of Douglas S. Johnson
Preface
Our first three installments on drug synthesis, Contemporary Drug Synthesis, The Art of Drug Synthesis, and Modern Drug Synthesis were published in 2004, 2007, and 2010, respectively. They have been warmly received by the chemistry community. The current title, Innovative Drug Synthesis, is our fourth installment of Wiley’s Drug Synthesis Series.
This book has six sections. Section I, “Infectious Diseases” covers five drugs; Section II, “Cancer” reviews five drugs, three of which are kinase inhibitors; Section III covers one drug that targets cardiovascular and metabolic diseases; Section IV on central nervous system diseases concerns four classes of recent drugs; Section V summarizes a new anti-inflammatory drug; and Section VI covers two additional drugs.
In addition to a detailed account of the drug synthesis, each chapter also covers background material on the drug class and/or disease indication, as well as key aspects relevant to the discovery of the drug, including, structure-activity relationships, pharmacokinetics, drug metabolism, efficacy and safety.
We are indebted to the contributing authors from both industry and academia. Many of them are veterans and well-known experts in medicinal chemistry. Some of them discovered the drugs that they reviewed. As a consequence, their work tremendously elevated the quality of this book. One of us (JJL) would like to thank his students, Elizabeth N. Cruz, Taylor D. Krueger, Cho K. Lai, Amanda N. Moules, Emily S. Murzinski, Karla E. Rodriguez, and Theresa V. Song for taking part in this writing project.
Meanwhile, we welcome your critique and suggestions so we can make this Drug Synthesis Series even more useful to the medicinal/organic chemistry community.
Jack Li and Doug JohnsonMay 1, 2015
Contributors
Dr. Nadia M. Ahmad
Vertex
86-88 Jubilee Avenue
Abingdon
Oxfordshire
OX14 4RW
United Kingdom
Dr. Christopher W. am Ende
Worldwide Medicinal Chemistry
Pfizer, Inc.
Eastern Point Road
Groton, CT 06340
United States
Dr. Makonen Belema
Bristol-Myers Squibb Co.
Virology Chemistry
5 Research Parkway
Wallingford, CT 06473
United States
Elizabeth N. Cruz
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Prof. Amy Dounay
Department of Chemistry and Biochemistry
Colorado College
14 East Cache La Poudre St.
Colorado Springs, CO 80903
United States
Dr. Robert W. Dugger
Chemical Research and Development
Pfizer, Inc.
Eastern Point Road
Groton, CT 06340
United States
Dr. Mark E. Flanagan
Worldwide Medicinal Chemistry
Pfizer, Inc.
Eastern Point Road
Groton, CT 06340
United States
Prof. Wenhao Hu
Institute for Advanced Interdisciplinary Research
East China Normal University
3663 North Zhongshan Road, Shanghai
P. R. China
Dr. Nathan D. Ide
Chemical Research and Development
Pfizer, Inc.
Eastern Point Road
Groton, CT 06340
United States
Ricky Anthony Jones
Chemical Research and Development
Pfizer, Inc.
Discovery Park
Sandwich, CT13 9NJ
United Kingdom
Taylor D. Krueger
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Dr. Pei-Pei Kung
Oncology Medicinal Chemistry
Pfizer, Worldwide Research and Development
San Diego, CA 92121
United States
Cho K. Lai
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Prof. Jie Jack Li
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Dr. Hui Liu
Peking University Shenzhen Graduate School
School of Chemical Biology and Biotechnology
Xili University Town, PKU Campus, F-210, Shenzhen, 518055
P. R. China
Dr. Shunying Liu
Institute for Advanced Interdisciplinary Research
East China Normal University
3663 North Zhongshan Road, Shanghai
P. R. China
Dr. Sha Lou
Process Research and Development
Bristol-Myers Squibb Company
New Brunswick, NJ 08901
United States
Dr. Nicholas Meanwell
Bristol-Myers Squibb Co.
Virology Chemistry
5 Research Parkway
Wallingford, CT 06473
United States
Amanda N. Moules
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Emily S. Murzinski
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Dr. Shawn Pack
Technical Operations
Janssen Pharmaceutica
Janssen-Pharmaceuticalaan 3
2440 Geel
Belgium
Dr. Zhengying Pan
Peking University Shenzhen Graduate School
School of Chemical Biology and Biotechnology
Xili University Town, PKU Campus, F-311, Shenzhen, 518055
P. R. China
Nandini C. Patel
Worldwide Medicinal Chemistry
Pfizer, Inc.
610 Main St.
Cambridge, MA 02139
United States
Dr. Paul Richardson
Oncology Medicinal Chemistry
Pfizer, Worldwide Research and Development
San Diego, CA 92121
United States
Karla E. Rodriguez
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Dr. Raymond F. Schinazi
Center for AIDS Research
Department of Pediatrics
Emory University School of Medicine
Atlanta, GA 30322
United States
Dr. Junxing Shi
CoCrystal Pharma, Inc.
Tucker, GA 30084
United States
Theresa V. Song
Department of Chemistry
University of San Francisco
2130 Fulton Street
San Francisco, CA 94117
United States
Dr. Peter L. Toogood
Lycera Corp
2800 Plymouth Road
NCRC
Ann Arbor, MI 48109
United States
Dr. Jamison B. Tuttle
Worldwide Medicinal Chemistry
Pfizer, Inc.
610 Main St.
Cambridge, MA 02139
United States
Dr. Rajappa Vaidyanathan
Process Research and Development
Bristol Myers Squibb
Building S11, Biocon Park
Jigani Link Road
Bommasandra IV
Bangalore 560099
India
Tony Whitaker
CoCrystal Pharma, Inc.
Tucker, GA 30084
United States
Dr. Ji Zhang
HEC R&D Center
Pharmaceutical Science
Process Research and Development
HEC–High-Tech Park, Dongguan
Guang Zhou, Guang-Dong Province
P. R. China
Dr. Yingjun Zhang
HEC R&D Center
Pharmaceutical Science
Process Research and Development
HEC–High-Tech Park, Dongguan
Guang Zhou, Guang-Dong Province
P. R. China
Part IInfectious Diseases
Chapter 1Entecavir (Baraclude): A Carbocyclic Nucleoside for the Treatment for Chronic Hepatitis B
Jie Jack Li
1 Background
Chronic hepatitis B virus (HBV) infection is a major global cause of morbidity and mortality. An estimated 400 million people worldwide have chronic HBV infection and more than half a million people die every year because of complications from HBV-related chronic liver disease such as liver failure and hepatocellular carcinoma (HCC). In the United States, 12 million people have been infected at some time in their lives with HBV. Of those individuals, more than 1 million people have subsequently developed chronic hepatitis B infection. These chronically infected persons are at highest risk of death from liver scarring (cirrhosis) and liver cancer. In fact, more than five thousand Americans die from hepatitis B-related liver complications each year. In many Asian and African countries where the HBV is endemic, up to 20% of the population may be carriers, and transmission occurs primarily through perinatal or early childhood infection. In some of these areas, the perinatal transmission rate may be as high as 90%!1–4
During the last 10 years, hepatitis B treatment has made significant progresses. For example, two biologics have been approved by the FDA, namely, interferon-α (IFN-α) and Pegylated-interferon-α (PEG-IFN-α). Also on the market are five small molecule antiviral agents for the treatment of chronic HBV, namely, entecavir (1), lamivudine (2), telbivudine (3), adefovir dipivoxil (4), and tenofovir (5).
As a biologic, INF-α is effective only in a subset of patients, is often poorly tolerated, requires parenteral administration, and is expensive. Hence, there is a need for alternative therapies for chronic hepatitis B. The introduction of lamivudine (2) in 1995, the first oral treatment for chronic HBV, ushered in a new era in the treatment of chronic hepatitis B when safe, effective, and well-tolerated oral medications were made available. It is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against both human immunodeficiency virus type 1 (HIV-1) and HBV. It has been used for the treatment of chronic hepatitis B at a lower dose than for the treatment of HIV, and it improves the seroconversion of e-antigen-positive hepatitis B and also improves histology staging of the liver. Unfortunately, long-term use of lamivudine (2) leads to emergence of a resistant HBV mutant (Tyr-Met-Asp-Asp, YMDD). Despite this fact, lamivudine (2) is still used widely as it is well tolerated.5
Telbivudine (3), a synthetic thymidine nucleoside analog, is the unmodified L-enantiomer of the naturally occurring D-thymidine. It prevents HBV DNA synthesis by acting as an HBV polymerase inhibitor. Within hepatocytes, telbivudine (3) is phosphorylated by host cell kinase to telbivudine-5′-triphosphate which, once incorporated into HBV DNA, causes DNA chain termination, thus inhibiting HBV replication. In this sense, telbivudine (3), like most nucleotide antiviral drugs, is a prodrug. Clinical trials have shown telbivudine (3) to be significantly more effective than lamivudine (2) or adefovir dipivoxil (4) and less likely to cause resistance.6
Adefovir dipivoxil (4) was initially developed as a treatment for HIV, but the FDA in 1999 rejected the drug due to concerns about the severity and frequency of kidney toxicity when dosed at 60 or 120 mg, respectively. However, 4 was effective at a much lower dose of 10 mg for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum alanine aminotransferases (primarily ALT) or histologically active disease. It works by blocking reverse transcriptase, an enzyme that is crucial for the HBV to reproduce in the body. Overall, the efficacy of 4 against wild-type and lamivudine (2)-resistant HBV and the delayed emergence of 4-resistance during monotherapy contribute to the durable safety and efficacy observed in a wide range of chronic hepatitis B patients.7
Tenofovir (5), a nucleotide analog closely related to adefovir dipivoxil (4) has been approved for the treatment of HBV in 2008, subsequent to its approval for the treatment of HIV infection in 2006. In vitro studies showed that it has activity against HBV with equimolar potency to 4. Clinical studies confirmed the efficacy of 5 in suppressing HBV replication, and it appears to be equally effective against both wild-type and lamivudine (2)-resistant HBV. The role of 5 in the rapidly expanding armamentarium of hepatitis B treatments will depend on the demonstration of long-term safety (renal and skeletal) and efficacy against wild-type HBV and HBV mutants that involve substitution of methionine within the YMDD motif, as well as a very low rate of resistance in NA-naïve as well as NA-experienced patients.8–10 NA stands for nucleos(t)ide analog.
The approval of the nucleotide and nucleoside analogs 1–5
