Anti-Inflammatory Drug Discovery

545 Pages·2012·64.193 MB·English

by  Jeremy I Levin, Stefan Laufer

RSC Drug Discovery
Edited by Jeremy I Levin and Stefan Laufer
Anti-Inflammatory
Drug Discovery
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Anti-Inflammatory Drug Discovery
RSC Drug Discovery Series
Editor-in-Chief:
Professor David Thurston, London School of Pharmacy, UK
Series Editors:
Dr David Fox, Pfizer Global Research and Development, Sandwich, UK
Professor Salvatore Guccione, University of Catania, Italy
Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain
Professor David Rotella, Montclair State University, USA
Advisor to the Board:
Professor Robin Ganellin, University College London, UK
Titles in the Series:
1: Metabolism, Pharmacokinetics 14: Neglected Diseases and Drug
and Toxicity of Functional Discovery
Groups 15: Biomedical Imaging
2:EmergingDrugsandTargetsfor 16: Pharmaceutical Salts and
Alzheimer’s Disease; Volume 1 Cocrystals
3:EmergingDrugsandTargetsfor 17: Polyamine Drug Discovery
Alzheimer’s Disease; Volume 2 18: Proteinases as Drug Targets
4: Accounts in Drug Discovery 19: Kinase Drug Discovery
5: New Frontiers in Chemical 20: Drug Design Strategies:
Biology Computational Techniques
6: Animal Models for and Applications
Neurodegenerative Disease 21: Designing Multi-Target Drugs
7: Neurodegeneration 22: Nanostructured Biomaterials
8: G Protein-Coupled Receptors for Overcoming Biological
9: Pharmaceutical Process Barriers
Development 23: Physico-Chemical and
10: Extracellular and Intracellular ComputationalApproachesto
Signaling DrugDiscovery
11: New Synthetic Technologies in 24: Biomarkers for Traumatic Brain
Medicinal Chemistry Injury
12: New Horizons in Predictive 25: Drug Discovery from Natural
Toxicology Products
13: Drug Design Strategies: 26: Anti-Inflammatory Drug
Quantitative Approaches Discovery
How to obtain future titles on publication:
A standing order plan is available for this series. A standing order will bring
delivery of each new volume immediately on publication.
For further information please contact:
BookSalesDepartment,RoyalSocietyofChemistry,ThomasGrahamHouse,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone],Fax:[phone],
Email:[email protected]
Visit our website at http://www.rsc.org/Shop/Books/
Anti-Inflammatory Drug
Discovery
Edited by
Jeremy I Levin
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
Stefan Laufer
Institute of Pharmacy, Tuebingen, Germany
RSCDrugDiscoverySeriesNo.26
ISBN: 978-1-84973-413-4
ISSN: 2041-3203
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
rTheRoyalSocietyofChemistry2012
Allrightsreserved
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Preface
Driven by the need for new orally active anti-inflammatory medicines, inten-
sive research is ongoing in both industry and academia on a diverse set of
biological pathways and targets with the goal of delivering therapeutics to
improve the lives of patients with conditions such as asthma, rheumatoid
arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, allergic dis-
eases, and pain. It was the goal of this volume to bring together respected
scientists who have been directly involved in these drug discovery efforts to
present the rationale for prosecuting specific targets, a current review of the
medicinal chemistry strategies that have been used, and the outcome of those
efforts.For someof these targets drugswith exciting potential have been deliv-
ered to clinical trials, while others have encountered unexpected roadblocks,
and both of those outcomes provide important lessons for today’s drug hun-
ters. It is our hope that the stories presented herein will serve as a valuable
resource for anyone interested in the discovery of new anti-inflammatory
drugs.
In addition, we would like to express our great appreciation to all of the
chapter authors for delivering clear, comprehensive reviews that will inform
andenlightenreadersonthestateoftheartintheirrespectiveareasofresearch.
We would also like to express our appreciation to Professor David Rotella
(Montclair State University), and Gwen Jones and Amaya Camara at RSC
Publishingfortheirhelp,supportandpatienceinthecourseofputtingtogether
this book.
Jeremy I. Levin, Ph.D.
Stefan Laufer, Ph.D.
RSCDrugDiscoverySeriesNo.26
Anti-InflammatoryDrugDiscovery
EditedbyJeremyILevinandStefanLaufer
rTheRoyalSocietyofChemistry2012
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
v

Contents
Introduction 1
Section 1: Arachidonic Acid Cascade
Chapter 1 Microsomal Prostaglandin E Synthase-1 7
2
Andreas Koeberle and Oliver Werz
1.1 Function of PGE as Bioactive Mediator 8
2
1.2 PGE Biosynthesis by mPGES-1 8
2
1.3 Structure and Biochemical Properties of mPGES-1 9
1.4 Regulation of mPGES-1 Expression 9
1.5 Redirection of the mPGES-1 Substrate PGH Due
2
to the Action of mPGES-1 Inhibitors 10
1.6 Determination of mPGES-1 Activity 10
1.7 mPGES-1 in Disease and Homeostasis – Results
from KO Studies 11
1.7.1 Inflammation, Fever and Pain 11
1.7.2 Neurological Diseases 11
1.7.3 Cancer 12
1.7.4 Renal and Cardiovascular System 12
1.8 Direct Inhibitors of mPGES-1 12
1.8.1 MK886 Derivatives 13
1.8.2 Phenanthreneimidazoles and Related
Compounds 14
1.8.3 Others 16
1.9 Dual Inhibitors of mPGES-1 and 5-LO 17
1.9.1 MK-886 and Derivatives 17
1.9.2 Pirinixic Acid Derivatives 18
1.9.3 Acylphloroglucinols 20
1.9.4 Others 20
RSCDrugDiscoverySeriesNo.26
Anti-InflammatoryDrugDiscovery
EditedbyJeremyILevinandStefanLaufer
rTheRoyalSocietyofChemistry2012
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
viii Contents
1.10 Selective Suppressors of mPGES-1 Expression 21
1.11 Conclusion 23
References 23
Chapter 2 Inhibitors of Cytosolic Phospholipase A a as
2
Anti-inflammatory Drugs 35
Matthias Lehr
2.1 Classification of the Phospholipase A Enzymes 35
2
2.2 Properties and Function of Cytosolic
Phospholipase A a 37
2
2.3 Assessment of cPLA a Inhibitors 38
2
2.4 Inhibitors of cPLA a 39
2
2.4.1 General 39
2.4.2 Trifluoromethyl Ketones and Methyl
Fluorophosphonates 39
2.4.3 a,b-Dioxoesters and a-Ketoamides 41
2.4.4 Benzhydrylindoles 41
2.4.5 Thiazolidinediones 45
2.4.6 (Aryloxy)propan-2-ones 46
2.4.7 Aryl Thiazolidinones 50
2.5 Conclusions 51
References 52
Chapter 3 Leukotriene A Hydrolase: Biology, Inhibitors and Clinical
4
Applications 58
Cheryl A. Grice, Anne M. Fourie and Alice Lee-Dutra
3.1 Background: Eicosanoids and Leukotrienes 58
3.2 Leukotriene A Hydrolase 61
4
3.3 LTA H – Pre-clinical and Human Genetic Rationale 62
4
3.3.1 Respiratory Disease 62
3.3.2 Gastrointestinal Disease 64
3.3.3 Inflammatory Arthritis 65
3.3.4 Cardiovascular Disease 66
3.3.5 Cancer 67
3.4 Small-molecule Approaches Targeting LTA H 68
4
3.4.1 X-ray Crystallography 69
3.4.2 G. D. Searle & Co. 70
3.4.3 Janssen Pharmaceutica NV 74
3.4.4 deCODE Genetics 81
3.4.5 Schering AG 84
3.4.6 Santen Pharmaceutical Co., Ltd 88
3.5 Clinical Evaluation of LTB Modulators 89
4
Contents ix
3.6 Summary 90
Acknowledgements 91
References 91
Chapter 4 CRTH2 Antagonists 104
L. Nathan Tumey
4.1 Role of PGD2 in Inflammation and Asthma 104
4.2 Receptors for PGD2: DP and CRTH2 105
4.3 Pharmacology of CRTH2 107
4.3.1 Role of CRTH2 in Animal Disease Models 107
4.3.2 Role of CRTH2 in Human Disease 109
4.4 CRTH2 Antagonists 109
4.4.1 Tricyclic Ramatroban Antagonists 110
4.4.2 Indole Acetic Acids and Related Antagonists 112
4.4.3 Phenoxyacetic Acids, Phenyl Acetic Acids
and Related Antagonists 115
4.4.4 Tetrahydroquinoline CRTH2 Antagonists 119
4.4.5 Dual CRTH2/DP Antagonists 120
4.5 Activity of CRTH2 Antagonists in Animal
Efficacy Studies 121
4.6 CRTH2 Biomarkers for Clinical Development 125
4.7 CRTH2 Antagonists in Clinical Development 125
4.8 Summary 127
References 127
Section 2: Kinases
Chapter5 DualInhibitionofPhosphodiesterase-4andp38MAPKinase:
AStrategyforTreatmentofChronicInflammatoryDiseases 137
Wolfgang Albrecht and Stefan Laufer
5.1 Introduction 137
5.2 p38 MAPK 138
5.3 Binding Modes of p38 MAPK Inhibitors 141
5.4 Clinical Development of p38 MAPK Inhibitors 144
5.5 Evidences for p38 MAPK as Key Enzyme in
Chronic Inflammation 146
5.6 New Indications for p38 MAPK Inhibitors 149
5.7 Therapeutic Potential of Drug Combinations with
p38 MAPK Inhibitors 149
5.8 Discovery and Development of PDE4 Inhibitors 150
5.9 Dual Inhibitors of p38 MAPK and PDE4 152
5.10 Conclusion 153
References 153