Phosphodiesterases and Their Inhibitors

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.

• List of Contributors XIPreface XVA Personal Foreword XVII1 Introduction 1Andrew S. Bell and Spiros Liras2 Toward a New Generation of PDE5 Inhibitors through Advances in Medicinal Chemistry 9Dafydd R. Owen2.1 Introduction 92.2 The First-Generation Agents 102.3 PDE5 as a Mechanism and Alternative Indications Beyond MED 112.4 A Summary of PDE5 Chemotypes Reported Post-2010 112.5 Second-Generation PDE5 Inhibitors from Pfizer: Pyrazolopyrimidines 122.6 Second-Generation PDE5 Inhibitors from Pfizer: Pyridopyrazinones 182.7 Conclusions 25References 253 PDE4: New Structural Insights into the Regulatory Mechanism and Implications for the Design of Selective Inhibitors 29Jayvardhan Pandit3.1 Introduction 293.2 Isoforms, Domain Organization, and Splice Variants 303.3 Structural Features of the Catalytic Site 313.4 Regulation of PDE4 Activity 323.5 Crystal Structure of Regulatory Domains of PDE4 333.6 UCR2 Interaction and Selectivity 383.7 Conclusions 39References 404 PDE4: Recent Medicinal Chemistry Strategies to Mitigate Adverse Effects 45Etzer Darout, Elnaz Menhaji-Klotz, and Thomas A. Chappie4.1 Introduction 454.2 Brief Summary of pan-PDE4 Inhibitors 464.2.1 Rolipram 474.2.2 Roflumilast 484.2.3 Cilomilast 484.2.4 Apremilast 494.3 PDE4 Strategies to Avoid Gastrointestinal Events 494.3.1 Allosteric Modulation 494.3.2 PDE4D Selectivity 534.3.3 Pfizer 534.3.4 Novartis 544.3.5 Merck-Frosst 544.3.6 GEBR-7b 554.3.7 PDE4B Selectivity 554.3.8 Asahi Kasei 564.3.9 GlaxoSmithKline 564.3.10 Pfizer 574.3.11 Tissue Targeting 574.3.12 Polypharmacology 584.3.13 Olanzapine Derivatives 584.4 Conclusions 59References 605 The Function, Enzyme Kinetics, Structural Biology, and Medicinal Chemistry of PDE10A 65Thomas A. Chappie and Patrick Verhoest5.1 Enzymology and Protein Structure 665.2 Papaverine-Related PDE10A Inhibitors 695.3 MP-10/PF-2545920 Class of Inhibitors 725.4 PF-2545920/MP-Inspired Inhibitors 745.5 PF-2545920/Papaverine/Quinazoline Hybrid Series of Inhibitors 755.6 PET Ligand Development 775.7 Summary and Future 79References 796 The State of the Art in Selective PDE2A Inhibitor Design 83Christopher W. am Ende, Bethany L. Kormos, and John M. Humphrey6.1 Introduction 836.2 Selective PDE2A Inhibitors 846.2.1 Bayer 846.2.2 Altana AG 856.2.3 Biotie Therapies 876.2.4 Boehringer Ingelheim 886.2.5 Janssen 896.2.6 Lundbeck 926.2.7 Merck 936.2.8 Neuro3d 956.2.9 Pfizer 956.3 Methods 1006.4 Conclusions 100References 1017 Crystal Structures of Phosphodiesterase 9A and Insight into Inhibitor Discovery 105Hengming Ke, Yousheng Wang, Yiqian Wan, and Hai-Bin Luo7.1 Introduction 1057.2 Subtle Asymmetry of the PDE9 Dimer in the Crystals 1057.3 The Structure of the PDE9 Catalytic Domain 1077.4 Interaction of Inhibitors with PDE9 1087.5 Implication on Inhibitor Selectivity 110References 1148 PDEs as CNS Targets: PDE9 Inhibitors for Cognitive Deficit Diseases 117Michelle M. Claffey, Christopher J. Helal, and Xinjun Hou8.1 PDE9A Enzymology and Pharmacology 1178.2 Crystal Structures of PDE9A Inhibitors 1198.3 Medicinal Chemistry Efforts toward Identifying PDE9A Inhibitors for Treating Cognitive Disorders 1208.3.1 Bayer 1208.3.2 Pfizer 1258.3.3 Boehringer Ingelheim 1298.3.4 Sun Yat-Sen University, China 1328.3.5 Envivo Pharmaceuticals 1338.4 Analysis of CNS Desirability of PDE9A Inhibitors 1358.5 Conclusions 135References 1379 Phosphodiesterase 8B 141Stephen W. Wright9.1 Introduction 1419.2 Identification 1419.3 Properties 1429.4 Expression and Tissue Distribution 1439.5 Functions of PDE8B 1439.5.1 Thyroid 1449.5.2 Adrenal Gland 1449.5.3 Pancreatic Islets 1449.6 Inhibitors and Potential Therapeutic Uses 145References 15010 Selective New Small-Molecule Inhibitors of Phosphodiesterase 1 155John M. Humphrey10.1 Introduction 15510.2 PDE1 Enzymology 15510.3 PDE1 Inhibitors 15610.3.1 Non-Selective PDE1 Inhibitors 15610.3.2 Selective PDE1 inhibitors 15810.4 Conclusion 161References 16311 Recent Advances in the Development of PDE7 Inhibitors 165Nigel A. Swain and Rainer Gewald11.1 Introduction 16511.1.1 PDE7: Subtypes and Distribution 16511.1.2 Rationale for PDE7 as a Therapeutic Target 16611.2 Historical Development of PDE7 Inhibitors 16611.2.1 Early Examples of Nonselective and Selective Lead Matter 16611.2.2 Developing Selective Lead Matter from Nonselective Hits 16711.2.3 Targeting PDE4/7 Dual Inhibitors 16811.3 Recent Advances in the Discovery of PDE7 Inhibitors for Peripheral Therapeutic Benefit 16911.3.1 PDE7 Inhibitors for the Treatment of T Cell-Related Disorders 16911.3.1.1 Developments in PDE7 Inhibitors for the Treatment of Airway-Related Disorders 17011.3.1.2 Developments in PDE7 Inhibitors for the Treatment of Nonairway-Related Disorders 17111.3.1.3 Summary of T-Cell-Related Research 17111.3.2 PDE7 Inhibitors for the Treatment of Neuropathic Pain 17211.4 Recent Advances in the Discovery of PDE7 Inhibitors for CNS-Related Disorders 17311.4.1 Creating PDE7 Inhibitors by Ligand-Based Virtual Screening Methods 17311.4.2 Repositioning PDE7 Inhibitors Designed for the Treatment of Peripheral Diseases 17611.5 Recent Advances in the Discovery of Dual PDE7 Inhibitors 17811.5.1 Dual PDE4/7 Inhibitors 17811.5.2 Dual PDE7/8 Inhibitors 18011.6 Identifying Next-Generation PDE7 Inhibitors 18111.6.1 Emerging Chemotypes as Novel PDE7 Inhibitors 18111.6.2 Novel Methods to Identify PDE7 Inhibitors 18211.6.2.1 Computational Methods to Identify New PDE7 Inhibitors 18211.6.2.2 Fission Yeast-Based HTS to Identify New PDE7 Inhibitors 18311.7 Summary 184References 18512 Inhibitors of Protozoan Phosphodiesterases as Potential Therapeutic Approaches for Tropical Diseases 191Jennifer L. Woodring and Michael P. Pollastri12.1 Introduction 19112.2 Malaria 19212.2.1 PfPDE Inhibition Studies 19312.3 Chagas Disease 19512.4 Leishmaniasis 19712.5 Human African Trypanosomiasis 20012.6 Conclusion 205References 206Index 211