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Phosphodiesterases and Their Inhibitors

Spiros Liras (Editor), Andrew S. Bell (Editor), Raimund Mannhold (Series Editor), Hugo Kubinyi (Series Editor), Gerd Folkers (Series Editor)
ISBN: 978-3-527-33219-9
240 pages
June 2014
Phosphodiesterases and Their Inhibitors (3527332197) cover image

Description

Written by the pioneers of Viagra, the first blockbuster PDE inhibitor drug.
Beginning with a review of the first wave of phosphodiesterase (PDE) inhibitors, this book focuses on new and emerging PDE targets and their inhibitors. Drug development options for all major human PDE families are discussed and cover diverse therapeutic fields, such as neurological/psychiatric, cardiovascular/metabolic, pain, and allergy/respiratory diseases. Finally, emerging chemotherapeutic applications of PDE inhibitors against malaria and other tropical diseases are discussed.
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Table of Contents

List of Contributors XI

Preface XV

A Personal Foreword XVII

1 Introduction 1
Andrew S. Bell and Spiros Liras

2 Toward a New Generation of PDE5 Inhibitors through Advances in Medicinal Chemistry 9
Dafydd R. Owen

2.1 Introduction 9

2.2 The First-Generation Agents 10

2.3 PDE5 as a Mechanism and Alternative Indications Beyond MED 11

2.4 A Summary of PDE5 Chemotypes Reported Post-2010 11

2.5 Second-Generation PDE5 Inhibitors from Pfizer: Pyrazolopyrimidines 12

2.6 Second-Generation PDE5 Inhibitors from Pfizer: Pyridopyrazinones 18

2.7 Conclusions 25

References 25

3 PDE4: New Structural Insights into the Regulatory Mechanism and Implications for the Design of Selective Inhibitors 29
Jayvardhan Pandit

3.1 Introduction 29

3.2 Isoforms, Domain Organization, and Splice Variants 30

3.3 Structural Features of the Catalytic Site 31

3.4 Regulation of PDE4 Activity 32

3.5 Crystal Structure of Regulatory Domains of PDE4 33

3.6 UCR2 Interaction and Selectivity 38

3.7 Conclusions 39

References 40

4 PDE4: Recent Medicinal Chemistry Strategies to Mitigate Adverse Effects 45
Etzer Darout, Elnaz Menhaji-Klotz, and Thomas A. Chappie

4.1 Introduction 45

4.2 Brief Summary of pan-PDE4 Inhibitors 46

4.2.1 Rolipram 47

4.2.2 Roflumilast 48

4.2.3 Cilomilast 48

4.2.4 Apremilast 49

4.3 PDE4 Strategies to Avoid Gastrointestinal Events 49

4.3.1 Allosteric Modulation 49

4.3.2 PDE4D Selectivity 53

4.3.3 Pfizer 53

4.3.4 Novartis 54

4.3.5 Merck-Frosst 54

4.3.6 GEBR-7b 55

4.3.7 PDE4B Selectivity 55

4.3.8 Asahi Kasei 56

4.3.9 GlaxoSmithKline 56

4.3.10 Pfizer 57

4.3.11 Tissue Targeting 57

4.3.12 Polypharmacology 58

4.3.13 Olanzapine Derivatives 58

4.4 Conclusions 59

References 60

5 The Function, Enzyme Kinetics, Structural Biology, and Medicinal Chemistry of PDE10A 65
Thomas A. Chappie and Patrick Verhoest

5.1 Enzymology and Protein Structure 66

5.2 Papaverine-Related PDE10A Inhibitors 69

5.3 MP-10/PF-2545920 Class of Inhibitors 72

5.4 PF-2545920/MP-Inspired Inhibitors 74

5.5 PF-2545920/Papaverine/Quinazoline Hybrid Series of Inhibitors 75

5.6 PET Ligand Development 77

5.7 Summary and Future 79

References 79

6 The State of the Art in Selective PDE2A Inhibitor Design 83
Christopher W. am Ende, Bethany L. Kormos, and John M. Humphrey

6.1 Introduction 83

6.2 Selective PDE2A Inhibitors 84

6.2.1 Bayer 84

6.2.2 Altana AG 85

6.2.3 Biotie Therapies 87

6.2.4 Boehringer Ingelheim 88

6.2.5 Janssen 89

6.2.6 Lundbeck 92

6.2.7 Merck 93

6.2.8 Neuro3d 95

6.2.9 Pfizer 95

6.3 Methods 100

6.4 Conclusions 100

References 101

7 Crystal Structures of Phosphodiesterase 9A and Insight into Inhibitor Discovery 105
Hengming Ke, Yousheng Wang, Yiqian Wan, and Hai-Bin Luo

7.1 Introduction 105

7.2 Subtle Asymmetry of the PDE9 Dimer in the Crystals 105

7.3 The Structure of the PDE9 Catalytic Domain 107

7.4 Interaction of Inhibitors with PDE9 108

7.5 Implication on Inhibitor Selectivity 110

References 114

8 PDEs as CNS Targets: PDE9 Inhibitors for Cognitive Deficit Diseases 117
Michelle M. Claffey, Christopher J. Helal, and Xinjun Hou

8.1 PDE9A Enzymology and Pharmacology 117

8.2 Crystal Structures of PDE9A Inhibitors 119

8.3 Medicinal Chemistry Efforts toward Identifying PDE9A Inhibitors for Treating Cognitive Disorders 120

8.3.1 Bayer 120

8.3.2 Pfizer 125

8.3.3 Boehringer Ingelheim 129

8.3.4 Sun Yat-Sen University, China 132

8.3.5 Envivo Pharmaceuticals 133

8.4 Analysis of CNS Desirability of PDE9A Inhibitors 135

8.5 Conclusions 135

References 137

9 Phosphodiesterase 8B 141
Stephen W. Wright

9.1 Introduction 141

9.2 Identification 141

9.3 Properties 142

9.4 Expression and Tissue Distribution 143

9.5 Functions of PDE8B 143

9.5.1 Thyroid 144

9.5.2 Adrenal Gland 144

9.5.3 Pancreatic Islets 144

9.6 Inhibitors and Potential Therapeutic Uses 145

References 150

10 Selective New Small-Molecule Inhibitors of Phosphodiesterase 1 155
John M. Humphrey

10.1 Introduction 155

10.2 PDE1 Enzymology 155

10.3 PDE1 Inhibitors 156

10.3.1 Non-Selective PDE1 Inhibitors 156

10.3.2 Selective PDE1 inhibitors 158

10.4 Conclusion 161

References 163

11 Recent Advances in the Development of PDE7 Inhibitors 165
Nigel A. Swain and Rainer Gewald

11.1 Introduction 165

11.1.1 PDE7: Subtypes and Distribution 165

11.1.2 Rationale for PDE7 as a Therapeutic Target 166

11.2 Historical Development of PDE7 Inhibitors 166

11.2.1 Early Examples of Nonselective and Selective Lead Matter 166

11.2.2 Developing Selective Lead Matter from Nonselective Hits 167

11.2.3 Targeting PDE4/7 Dual Inhibitors 168

11.3 Recent Advances in the Discovery of PDE7 Inhibitors for Peripheral Therapeutic Benefit 169

11.3.1 PDE7 Inhibitors for the Treatment of T Cell-Related Disorders 169

11.3.1.1 Developments in PDE7 Inhibitors for the Treatment of Airway-Related Disorders 170

11.3.1.2 Developments in PDE7 Inhibitors for the Treatment of Nonairway-Related Disorders 171

11.3.1.3 Summary of T-Cell-Related Research 171

11.3.2 PDE7 Inhibitors for the Treatment of Neuropathic Pain 172

11.4 Recent Advances in the Discovery of PDE7 Inhibitors for CNS-Related Disorders 173

11.4.1 Creating PDE7 Inhibitors by Ligand-Based Virtual Screening Methods 173

11.4.2 Repositioning PDE7 Inhibitors Designed for the Treatment of Peripheral Diseases 176

11.5 Recent Advances in the Discovery of Dual PDE7 Inhibitors 178

11.5.1 Dual PDE4/7 Inhibitors 178

11.5.2 Dual PDE7/8 Inhibitors 180

11.6 Identifying Next-Generation PDE7 Inhibitors 181

11.6.1 Emerging Chemotypes as Novel PDE7 Inhibitors 181

11.6.2 Novel Methods to Identify PDE7 Inhibitors 182

11.6.2.1 Computational Methods to Identify New PDE7 Inhibitors 182

11.6.2.2 Fission Yeast-Based HTS to Identify New PDE7 Inhibitors 183

11.7 Summary 184

References 185

12 Inhibitors of Protozoan Phosphodiesterases as Potential Therapeutic Approaches for Tropical Diseases 191
Jennifer L. Woodring and Michael P. Pollastri

12.1 Introduction 191

12.2 Malaria 192

12.2.1 PfPDE Inhibition Studies 193

12.3 Chagas Disease 195

12.4 Leishmaniasis 197

12.5 Human African Trypanosomiasis 200

12.6 Conclusion 205

References 206

Index 211

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Author Information

Spiros Liras is the head of the cardiovascular metabolic and endocrine diseases (CVMED) medicinal chemistry department at Pfizer R&D in Cambridge, MA (USA). Previously, he was Senior Director of medicinal chemistry in Neuroscience at Pfizer, working on treatments for addiction, depression, schizophrenia, cognition and Alzheimer's disease. In Neuroscience he worked on multiple PDE targets for the treatment of neuropsychiatric diseases including PDE10, PDE9, PDE2 and PDE1. Dr. Liras obtained his PhD in organic chemistry in 1989 from Iowa State University. He joined Pfizer in 1994 after postdoctoral studies at the University of Texas at Austin. He is a coauthor in more than 70 publications and patents.

Andrew Bell was with Pfizer for over 30 years, following studies at York University (UK). He spent his early career working on PDE inhibitors leading to the inotrope/ vasodilator (PDE3) candidate, nanterinone, and the PDE5 inhibitor, sildenafil (Viagra, Revatio). Soon after the launch of sildenafil in 1998, he was given responsibility for File Enrichment, as part of Pfizer's collaborations with ArQule and Tripos. He has subsequently applied the results of the File Enrichment investment to generate new lead series for multiple projects, including novel series of selective PDE- 4,5,8 and 9 inhibitors. He is currently involved in research into parasitic diseases at Imperial College, London.
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