Pain Therapeutics Current and Future Treatment Paradigms 1 0 0 P F 5- 1 7 7 3 7 9 4 8 1 8 7 9 9/ 3 0 1 0. 1 oi: d g | or c. s s.r b u p p:// htt n o 3 1 0 2 er b m e v o N 4 . n 0 o d e h s bli u P View Online RSC Drug Discovery Series Editor-in-Chief: Professor David Thurston, King’s College, London, UK Series Editors: 1 00 Dr David Fox, Vulpine Science and Learning, UK P F Professor Ana Martinez, Medicinal Chemistry Institute-CSIC, Madrid, Spain 5- 1 Professor David Rotella, Montclair State University, USA 7 7 73 Advisor to the Board: 9 4 8 Professor Robin Ganellin, University College London, UK 1 8 97 Titles in the Series: 9/ 03 1:Metabolism,Pharmacokineticsand 20:DrugDesignStrategies: 1 0. ToxicityofFunctionalGroups ComputationalTechniques 1 oi: 2:EmergingDrugsandTargetsfor andApplications d Alzheimer’sDisease;Volume1 21:DesigningMulti-TargetDrugs org | 3:EmergingDrugsandTargetsfor 22:NanostructuredBiomaterialsfor c. 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PublishedbyTheRoyalSocietyofChemistry, ThomasGrahamHouse,SciencePark,MiltonRoad, CambridgeCB40WF,UK RegisteredCharityNumber207890 Forfurtherinformationseeourwebsiteatwww.rsc.org 5 0 0 P F 5- 71 Preface 7 3 7 9 4 8 1 8 7 9 9/ 3 0 1 0. 1 oi: Pain continues to be a dominant issue for healthcare worldwide as a key d g | symptomassociated withnearly every diseasestate.Opiates and non-steroidal or anti-inflammatory drugs (NSAIDs) remain as the market-leading analgesics, c. s.rs despite leaving large numbers of patients ineffectively treated and exposed to b u significantsafetyconcerns.Painresearchhasbeenactiveoverthelastdecadein p p:// thesearchfornovelmedicinestofillthisgap,but,disappointingly,thishasnot htt translated to the approval of many novel pain analgesics with differentiated n 3 o efficacyandsafetyprofiles.Morerecently,therehasbeenashiftawayfromthe 1 0 research strategies underwritten by preclinical models of efficacy and treating 2 er painasauniform condition,towardsstrategies basedonhumanconfidencein b m e rationale, underwritten by human translation strategies and an understanding v No of the role of the target in the pathophysiology of the disease, to enable the . n 04 selection of the right patient populations for clinical trials. These evolving o strategiesgiveusrenewedconfidencethatwewillsoonseetheadvancementof d he differentiated pain medications towards regulatory approval. s bli This book is a contemporary review of the field of pain therapeutics, u P including the historical medicines which still dominate standard-of-care treatments, such as opiates and NSAIDs, as well as the new mechanisms and combinations/reformulations that have dominated the regulatory approvals overthelastdecade,suchasLyricasandthenewformulationofOxyContins. In addition, several of the chapters cover targets and mechanisms that have been explored as potential treatments of pain with limited success so far, such as delta-opioid ligands, although there are notable exclusions such as the area of purinergic receptors since these have been reviewed extensively elsewhere. Finally coverage is provided of the new emerging mechanisms currently providing excitement in the field of pain research, such as selective sodium channel modulators and biased opiate ligands. RSCDrugDiscoverySeriesNo.35 PainTherapeutics:CurrentandFutureTreatmentParadigms EditedbyCharlotteAllerton rTheRoyalSocietyofChemistry2014 PublishedbytheRoyalSocietyofChemistry,www.rsc.org v View Online vi Preface Throughoutthisbookthechallengesinpainresearchthathaveunderwritten thelackofsuccessindeliveringnewanalgesicstopatientsarehighlighted,such asthelackoftranslationseenwithpre-clinicalmodelstothecurrentregulatory and commercial challenges, as well as the changes in strategies that are being 5 0 adopted to ensure greater success in the future. Finally, the book covers case 0 P F studies oftwonovelproductsapprovedduring thelastdecade,Lyrica andthe 15- Butranss patch, which provide insights into the discovery and development 7 7 3 journey for both an oral and non-oral product. 7 9 4 Mythanksandappreciationgotoalloftheauthorsforthehugeeffortthey 8 1 8 have put into providing comprehensive and enlightening chapters in the 7 9 9/ important areas of pain research and development; as well as to Rosalind 3 10 Searle and Gwen Jones for their continued guidance on behalf of the Royal 0. 1 Society of Chemistry. oi: d org | Charlotte Allerton c. s s.r b u p p:// htt n o 3 1 0 2 er b m e v o N 4 . n 0 o d e h s bli u P 7 0 0 P F 5- 71 Contents 7 3 7 9 4 8 1 8 7 9 9/ 3 0 1 Chapter 1 The Disease of Pain and Current Market Trends 1 0. oi:1 Charlotte M. N. Allerton, Zahid Ali and Devyn M. Smith d g | or 1.1 Introduction 1 sc. 1.2 The Disease of Pain 2 s.r b 1.2.1 Acute and Chronic Pain 2 u p p:// 1.2.2 Mechanisms Underlying Pain 3 htt 1.3 Recent Trends in Pain Research 5 on 1.3.1 Pain Research over the Last Decade 5 3 1 1.3.2 Dominant Pain Treatments Over the 0 2 er Last Decade 8 b m 1.3.3 Recent Trends in the Regulatory, Payer and e ov Commercial Environment 13 N 4 1.4 Future Trends in Pain Research 16 . n 0 1.4.1 New Trends in Preclinical Research Strategies 16 o ed 1.4.2 Summary of Emerging Mechanisms 18 h s bli 1.4.3 Optimising Early Analgesic Clinical Trials 22 u P 1.4.4 Emerging Trends in the Pain Market 27 1.5 Conclusions 31 References 32 Chapter 2 Oral Opioids 37 Veeraindar Goli, David Pryde and KiyoOmoto 2.1 Introduction 37 2.2 Opiate Pharmacology and Medicinal Chemistry 38 2.2.1 Opioids and Opiates 38 2.2.2 Opioid Receptors and Their Pharmacology 39 2.2.3 Opioid Receptor Mediated Side Effects 40 2.2.4 MOP Receptor Ligands 41 RSCDrugDiscoverySeriesNo.35 PainTherapeutics:CurrentandFutureTreatmentParadigms EditedbyCharlotteAllerton rTheRoyalSocietyofChemistry2014 PublishedbytheRoyalSocietyofChemistry,www.rsc.org vii View Online viii Contents 2.2.5 DOP Receptor Ligands 47 2.2.6 KOP Receptor Ligands 48 2.2.7 NOP Receptor Ligands 50 2.2.8 Peptide Ligands 55 7 0 2.2.9 Opioid Receptor Structural Biology 56 0 P F 2.3 Clinical Overview 60 5- 1 2.3.1 Rationale 60 7 7 3 2.3.2 Guidelines 61 7 9 4 2.3.3 Clinical Pharmacology 63 8 1 8 2.3.4 Clinical Considerations 66 7 9 9/ 2.3.5 Pure Agonist Opioids 69 3 10 2.3.6 Partial Agonists 74 0. 1 2.3.7 Agonist-Antagonists 75 doi: 2.3.8 Antagonists 76 org | 2.3.9 Dual-Pharmacology Opiate Drugs 76 c. 2.3.10 Oral Reformulations and Tamper-Resistant s bs.r Formulations 81 u p://p 2.4 New Opiate Research 87 htt 2.4.1 Functionally Biased Ligands 87 n 2.4.2 Splice Variants, Heterodimers o 13 and SNPs 87 0 er 2 2.4.3 Conjugated Analogues for Peripheral mb Restriction 88 e v 2.4.4 Opioid Activation of the Immune Pathway 88 o N 4 2.5 Conclusions 89 . n 0 References 89 o d e h s bli Pu Chapter 3 Anti-Inflammatory Drugs 105 Ariamala Gopalsamy and Suvit Thaisrivongs 3.1 Introduction 105 3.2 Corticosteroids 107 3.2.1 Mechanism of Action 108 3.2.2 Resistance and Side Effects 108 3.2.3 Dissociated Ligand of GC Receptor 108 3.3 Disease-Modifying Anti-Rheumatic Drugs 110 3.3.1 Methotrexate 111 3.3.2 Other DMARDs 112 3.3.3 Combination Therapies 112 3.4 Non-Steroidal Anti-Inflammatory Drugs 112 3.4.1 NSAIDs—Mechanism of Action 112 3.4.2 NSAIDs—Adverse Effect 113 3.4.3 Selective COX-2 Inhibitors (Coxibs) 114 3.4.4 COX-2—Adverse Effects 115 3.4.5 Alternatives to NSAIDs and Coxibs 115 View Online Contents ix 3.5 Inflammatory Kinases 115 3.5.1 p38 Kinase Inhibitors 116 3.5.2 Bruton’s Tyrosine Kinase Inhibitors 118 3.5.3 Spleen Tyrosine Kinase (SYK) Inhibitors 121 7 0 3.5.4 Janus Tyrosine Kinase (JAK) Inhibitors 123 0 P F 3.6 Conclusion 126 5- 1 List of Abbreviations 127 7 7 3 Acknowledgement 127 7 9 4 References 127 8 1 8 7 9 9/ 3 0 1 0. Chapter 4 Ion Channel Modulators 131 1 oi: Karl R. Gibson, Peter J. Cox, Edward Stevens, d g | Wendy J. Winchester, Aaron C. Gerlach, Brian E. Marron or c. and Richard P. Butt s s.r b u p 4.1 Introduction—The Role of Ion Channels in Pain 131 p:// 4.2 TRP Channels as Nociceptor Terminal htt n Excitators—Signal Generation 134 o 13 4.2.1 TRPV1 135 0 er 2 4.2.2 TRPA1 137 b 4.2.3 TRPV2 140 m ve 4.2.4 TRPV3 140 o N 4 4.2.5 TRPV4 141 . n 0 4.2.6 TRPM8 142 o d 4.3 Voltage-Gated Sodium Channels—Signal e h blis Transduction and Conduction 143 Pu 4.3.1 NaV Channel Structure 143 4.3.2 Non-selective Na Modulators 144 V 4.3.3 Na 1.3 145 V 4.3.4 Na 1.7 146 V 4.3.5 Na 1.8 148 V 4.3.6 Na 1.9 149 V 4.4 Potassium Channels as Pain Targets 150 4.4.1 Introduction to Voltage-Gated Potassium Channels 150 4.4.2 K 7 channels 151 V 4.5 Calcium Channel Modulators as Pain Treatments 154 4.5.1 Introduction to Voltage-Gated Calcium Channels 154 4.5.2 N-type Calcium Channels 155 4.5.3 Other VGCCs as Pain Targets 157 4.5.4 a d Ligands as VGCC Modulators 157 2 4.6 Challenges and Future Perspectives 159 References 159 View Online x Contents Chapter 5 Neurotransmitters and Other Non-Opiate Central Mechanisms 171 Simon E. Ward 7 0 5.1 Introduction 171 0 P F 5.2 Role of Central Mechanisms in Pain 172 5- 1 5.2.1 Ascending Pain Pathways 172 7 7 3 5.2.2 Descending Pain Pathways 173 7 9 4 5.3 Reuptake Inhibitors 175 8 1 8 5.3.1 Selective Serotonin Reuptake 7 9 9/ Inhibitors 176 3 10 5.3.2 Mixed Serotonin and Norepinephrine 0. 1 Reuptake Inhibitors 178 doi: 5.3.3 Next-Generation Reuptake Inhibitors 179 org | 5.4 Alpha2A Agonists 180 c. 5.5 NMDA Receptor Antagonists 181 s bs.r 5.6 GABA Receptor Modulators 183 u p://p 5.7 Cannabinoid Receptor Agonists/Modulators 185 htt 5.8 Adenosine Agonists 190 n 5.9 Future Perspectives 191 o 13 References 191 0 2 er b m e v o N Chapter 6 Biotherapeutics for the Treatment of Pain 197 4 . n 0 Gregory J. Carven and Lee R. Roberts o d e sh 6.1 Introduction 197 ubli 6.2 Antibodies and Antibody-Related Molecules 198 P 6.3 Targeting Neurotrophins and Neurotrophin Receptors 199 6.3.1 Antibodies Against Nerve Growth Factor 200 6.3.2 Nerve Growth Factor Blockade by other Modalities 201 6.3.3 Modulation of TrkA 201 6.4 Targeting Proinflammatory Cytokines with Biotherapeutics 202 6.4.1 Tumour Necrosis Factor 203 6.4.2 Interleukin-6 204 6.4.3 Interleukin-1b 205 6.5 Targeting Ion Channels with Antibodies 205 6.6 Peptide Conjugates 207 6.7 Gene Therapy 209 6.8 Non-Antibody Protein Therapeutics 211 6.9 Future Directions for Pain Biotherapeutics 211 References 211