Neurodegenerative Diseases (eBook)

Topics in Medicinal ChemistryAlso Available Electronically 8
Aims and Scope 8
Preface to the Series 10
Foreword to Volume 6 12
Contents 18
The Role of Histone Deacetylases in Neurodegenerative Diseases and Small-Molecule Inhibitors as a Potential Therapeutic Approach 20
1 Neurodegeneration 22
2 Overview of Histone Deacetylases 23
2.1 Classification 23
2.2 Structural Aspects of Zinc-Dependent Histone Deacetylases 27
2.3 General Overview of Known Class I, II, and IV HDAC Inhibitors 28
2.3.1 Introduction 28
2.3.2 Hydroxamic Acids 29
2.3.3 Ortho-N-Acyl-Phenylene Diamines 30
2.3.4 Ortho-N-Acyl-Phenolamines 30
2.3.5 Macrocyclic Natural Products 31
2.3.6 Ketones and Trifluoromethyl Ketones 32
2.3.7 Carboxylic Acids 33
2.3.8 Selectivity Determination 34
2.4 The Sirtuins (Class III HDACs) 35
2.4.1 Structure, Mechanism, and Function of Sirtuins 35
2.4.2 Sirtuin Inhibitors 36
2.4.3 Sirtuin Activators 38
3 Potential Treatment of Neurodegenerative Disorders with HDAC Inhibitors 40
3.1 Introduction 40
3.2 HDACs, Chromatin Remodeling, and Control of the Epigenome 40
3.3 Control and Dysregulation of Gene Transcription in Neurodegeneration 41
3.4 Sequestration of HATs and Transcriptional Factors in Neurodegeneration 42
3.5 HDAC Inhibitors Ameliorate Transcriptional Dysregulation 44
4 Effect of HDAC Inhibitors on Reversing Protein Accumulation in Neurodegeneration 47
4.1 The Role of the Ubiquitin-Proteosome System and Autophagy Pathways 47
4.2 Regulation of Protein Turnover by HATS and HDACs 48
4.3 Effect of SUMO E3 Ligase Activity of Class IIa HDACs 49
4.4 HDAC6: A Master Regulator of Cell Response to Cytotoxic Insults 50
4.5 HDACs and Sirtuins Regulate Autophagy Pathways 52
5 Neuroprotection Through HDAC Inhibition 53
5.1 Introduction 53
5.2 Neuroprotection by Sirtuins 54
6 Treating Cognitive Impairment and Depression with HDAC Inhibitors 56
6.1 Introduction 56
6.2 Procognitive Effects of HDAC Inhibition 56
6.3 Antidepressant Effects of HDAC Inhibition 60
7 Conclusion 60
References 61
Phosphodiesterase Inhibition to Target the Synaptic Dysfunction in Alzheimer´s Disease 76
1 Introduction 77
2 AD as a Disease of Synaptic Dysfunction 79
2.1 Synapse Loss in AD 79
2.2 Abeta and Synapse Function 80
2.3 Synapse Loss as Both Cause and Effect in AD 80
3 Cyclic Nucleotides and Synaptic Plasticity 82
3.1 cAMP 83
3.2 cGMP 84
4 The Phosphodiesterases 84
4.1 Enzyme Structure and Function 84
4.2 Compartmentalization of PDE Signaling 86
4.3 PDE4 87
4.4 PDE7 and PDE8B 90
4.5 PDE5A 92
4.6 PDE9A 93
4.7 PDE2A 97
5 Perspective 101
References 103
Glutamate and Neurodegenerative Disease 110
1 Introduction 111
2 NMDA Receptors 113
2.1 NMDA Receptor Biology 113
2.2 NMDA Receptor Modulators 117
3 AMPA Receptors 119
3.1 AMPA and Kainate Receptor Biology 119
3.2 AMPA Receptor Modulators 123
4 Metabotropic Glutamate Receptors 127
4.1 Metabotropic Glutamate Receptor Biology 127
4.2 Metabotropic Glutamate Receptor Modulators 130
4.2.1 mGluR1 131
4.2.2 mGluR2 and 3 133
4.2.3 mGluR4 136
4.2.4 mGluR5 137
4.2.5 mGluR 6, 7, and 8 142
5 Glutamate Transporters 143
5.1 Glutamate Transporter Biology and the Role of Astrocytes 143
5.2 Glutamate Transporter Modulators 146
6 Conclusion 147
References 147
Modulation of the Kynurenine Pathway for the Potential Treatment of Neurodegenerative Diseases 167
1 Introduction 168
2 Tryptophan Metabolism and the Kynurenine Pathway 168
3 Introduction of KP Enzymes and Key Metabolites 169
4 Physiological and Pathological Features of KP Pathway 170
4.1 Physiological Role 170
4.2 Kynurenines and CNS Dysfunction 171
4.3 Kynurenine Pathway and Disease 173
5 Enzymes in the KP as Drug Targets and Their Inhibitors 173
5.1 Indoleamine 2,3-Dioxygenase 174
5.2 KAT II Inhibitors 176
5.3 Kynureninase Inhibitors 177
5.4 3-Hydroxyanthranilic Acid Oxygenase Inhibitors 178
5.5 KMO Inhibitors 178
5.6 KMO Inhibition and Stroke/Ischemia 181
5.7 KMO Inhibition and Huntington´s Disease 182
5.7.1 Optimization of KMO Inhibitors for the Potential Treatment of HD 183
6 Perspective and Future Challenges 187
References 189
Spinal Muscular Atrophy: Current Therapeutic Strategies 195
1 Introduction 196
2 SMA Genetics 196
3 SMA Diagnosis and Categorization 197
4 Current Treatments 197
4.1 Preclinical Evaluation 197
4.1.1 In Vitro and Ex Vivo Assays 197
4.1.2 In Vivo Models 198
4.2 Supportive Treatments 199
4.3 Investigational Therapies 199
4.3.1 Biological Strategies for the Treatment of SMA 199
4.3.2 Small Molecule Agents 200
HDAC Inhibitors 201
Antibiotics and Their Derivatives 203
Agents that Inhibit the Decapping Scavenger Enzyme 204
Natural Polyphenols 205
Other Chemical Agents 205
5 Target Product Profile for an SMA Therapeutic 206
6 Conclusions 206
References 207
Index 210