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1 Introduction / Andrew S. Bell Bell, Andrew S., Spiros Liras Liras, Spiros 1 -- 2 Toward a New Generation of PDE5 Inhibitors through Advances in Medicinal Chemistry / Dafydd R. Owen Owen, Dafydd R. 9 -- 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 / Jayvardhan Pandit Pandit, Jayvardhan 29 -- 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 / Etzer Darout Darout, Etzer, Elnaz Menhaji-Klotz Menhaji-Klotz, Elnaz, Thomas A. Chappie Chappie, Thomas A. 45 -- 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 Gastiointestinal 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 Glaxo Smith Kline 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 / Thomas A. Chappie Chappie, Thomas A., Patrick Verhoest Verhoest, Patrick 65 -- 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 / Christopher W. am Ende Ende, Christopher W. am, Bethany L. Kormos Kormos, Bethany L., John M. Humphrey Humphrey, John M. 83 -- 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 Jaussen 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 / Hengming Ke Ke, Hengming, Yousheng Wang Wang, Yousheng, Yiqian Wan Wan, Yiqian, Hai-Bin Luo Luo, Hai-Bin 105 -- 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 / Michelle M. Claffey Claffey, Michelle M., Christopher J. Helal Helal, Christopher J., Xinjun Hou Hou, Xinjun 117 -- 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 |
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-- 8.3.3 Boehringer Ingelheim 129 -- 8.3.4 SunYat-Seri University, China 132 -- 8.3.5 Envivo Pharmaceuticals 133 -- 8.4 Analysis of CNS Desirability of PDE9A Inhibitors 135 -- 8.5 Conclusions 135 -- References 237 -- 9 Phosphodiesterase 8B / Stephen W. Wright Wright, Stephen W. 141 -- 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 / John M. Humphrey Humphrey, John M. 155 -- 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 / Nigel A. Swain Swain, Nigel A., Rainer Gewald Gewald, Rainer 165 -- 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 -- 1.1.6.1 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 / Jennifer L. Woodring Woodring, Jennifer L., Michael P. Pollastri Pollastri, Michael P. 191 -- 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. |
