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pages ; [ca. 23-29] cm
  • Pharmacotherapy, Toxicodynamics and Regulatory Science-Divergent Objectives Nonclinical Pharmacokinetics - a primer Routes - with considerations for species specificity Delivery Systems Regimens Fundamentals of Nonclinical Formulation Excipients and Vehicles: Tolerance and toxicity Appendices.
  • (source: Nielsen Book Data)9781466502536 20171218
If we will ever achieve Paul Ehrlich's "magic bullet, " that is, a molecule which goes with high selectivity to the therapeutic target site, does what it needs to do, and is subsequently cleared from the body, the practice of safety assessment will have to change. Nonclinical Drug Administration: Formulations, Routes and Regimens for Solving Drug Delivery Problems in Animal Model Systems seeks to address a trio of objectives that, though separate, are linked and central to biomedical science and, ultimately, medicine. Rather seeing these as separate "silos, " those working in nonclinical safety assessment will have to view these three in an integrated manner and to regularly and thoughtfully incorporate new information and technology. The trio of objectives this book explores are: first, to present how to deliver more of a drug product systemically to facilitate the regulatory need for evaluating safety and efficacy in animal species (at elevated exposure levels) prior to advancing the drug to human testing; second is to achieve better tolerance to therapeutics administration in test animals and humans which achieves objectives 1 and 3; and third, to explore ways to improve on therapeutic target receptor delivery performance, therefore improving both clinical pharmacodynamics bioavailability and specificity. The book's ten chapters assemble the basic concepts, principles and hypotheses involved in quantitative receptor and chronological organism interaction dynamics central to the successful development of new therapeutics which depend on systemic administration to achieve desired therapeutic goals and in so doing avoid outcomes which limit, marginalize, or preclude the therapeutic use of so many molecules.
(source: Nielsen Book Data)9781466502536 20171218
The concept of the perfect medicine as a molecule that goes with high selectivity to the therapeutic target site, does what it needs to do, and is subsequently cleared from the body is especially relevant now. Much of the current costs and post-market safety concerns arise from the inability to achieve adequate concentrations and selectivity in the due course of actually delivering the active drug. Providing an integrated approach, this book presents ways of achieving the desired adequate and selective delivery using the currently available technology in three tool sets: route, regimen, and formulation.
(source: Nielsen Book Data)9781466502598 20171218
352 pages : 287 b/w images, 3 tables, 4 halftones and 283 line drawings ; cm.
This book compiles reliable protocols for preparation of intermediates for carbohydrate synthesis or other substances and methods performed at the bench, which can be expected to be useful in the glycosciences. To ensure reproducibility, the experimental part involved is verified by an independent checker by repeating the protocol or using the method. Regardless of whether the method has previously been published, the protocol must be reliable and expected to be of wide use in the carbohydrate field.
(source: Nielsen Book Data)9781498726924 20171218
1 online resource (8 volumes) : illustrations (some color)
  • Volume 1: General Perspective - The Future of Drug Discovery Volume 2: Drug Discovery Technologies Volume 3: In Silico Drug Discovery Tools Volume 4: Experimental ADME and Toxicology Volume 5: Cancer, Immunology and Inflammation, and Infectious Disease Volume 6: CNS, Pain, Metabolic Syndrome, Urology, Gastrointestinal and Cardiovascular Volume 7: Biologics Medicine Volume 8: Case Histories in Recent Drug Discovery.
  • (source: Nielsen Book Data)9780128032008 20170724
Comprehensive Medicinal Chemistry III, Third Edition provides a contemporary and forward looking critical analysis and summary of recent developments, emerging trends, and recently identified new areas where medicinal chemistry is having an impact. The discipline of medicinal chemistry continues to evolve as it adapts to new opportunities and strives to solve new challenges. These include drug targeting, biomolecular therapeutics, development of chemical biology tools, data collection and analysis, in silico models as predictors for biological properties, identification and validation of new targets, approaches to quantify target engagement, new methods for synthesis of drug candidates such as green chemistry, development of novel scaffolds for drug discovery, and the role of regulatory agencies in drug discovery.
(source: Nielsen Book Data)9780128032008 20170724
pages ; cm
  • Introduction: Hydrogel as useful carrier for drug delivery systems: an overview. Synthesis of protein-based hydrogels as drug delivery devices. Synthesis of polysaccharide-based hydrogels as drug delivery devices. Synthetic hydrogels as drug delivery devices. Nanocomposite hydrogels: Synthesis and characterization. pH-sensitive drug-delivery hydrogels: synthesis and applications. Thermo-sensitive drug-delivery hydrogels: synthesis and applications. Enzyme-responsive hydrogels: synthesis and applications. Nanocomposites hydrogels as electro and magneto-responsive devices. Multi-responsive drug delivery hydrogels. Mucoadhesive Hydrogels: a valuable strategy for the prolonged-delivery of drugs. Hydrogel as carrier for large-molecule delivery. DNA delivery vectors for gene-therapy. Synthesis and application of molecularly imprinted hydrogels for specific release of the therapeutics.
  • (source: Nielsen Book Data)9781498749022 20171218
The book deals with the synthesis and characterization of hydrogels specifically used as drug delivery systems. Each chapter includes the most recent updates about the different starting materials employed-whether natural and synthetic-and the improvement, such as modifications of synthetic approach and polymerization technique, of their physicochemical and biological properties to synthetize high performing carriers for specific uses, i.e. stimuli-responsive materials, molecularly imprinted polymers, mucoadhesive materials, carrier for the delivery of high molecular weight drugs, and gene-delivery.
(source: Nielsen Book Data)9781498749022 20171218
1 online resource.
This third volume in a four-volume set offers new theories and applications for the diagnosis and treatment of mental disorders. Having laid the groundwork in the first two volumes, the authors now embark on significant, real-life scenarios that apply their philosophy to mental disorder treatments. The goal of the project is to take the industry toward sustainability, not just in terms of the chemical engineering used to create medicines, but also environmentally, economically, and personally. Their unique approach uses a more holistic and philosophically cohesive method for treating mental disorders, making the industry "greener" and the patient healthier. The four volumes in "The Greening of Pharmaceutical Engineering" are: * Volume 1: Practice, Analysis, and Methodology * Volume 2: Theories and Solutions * Volume 3: Applications for Mental Disorder Treatments * Volume 4: Applications for Physical Disorder Treatments This ground-breaking set of books is a unique and state-of-the-art study that only appears here, within these pages. A fascinating study for the engineer, scientist, and pharmacist working in the pharmaceutical industry and interested in sustainability, it is also a valuable textbook for students and faculty studying these subjects.
(source: Nielsen Book Data)9781119183815 20170807
1 online resource (xv, 177 pages) : illustrations.
  • Introduction to Hazardous Reagent Substitution in the Pharmaceutical Industry-- Recyclability of Reagents-- Recoverable Polymer-supported DMAP Derivatives-- Synthesis of Atorvastatin-- Synthesis of Raloxifene-- Synthesis of Montelukast-- Development of a Safe, Scalable, Azide-free Synthesis of 1-Aryl-1H-tetrazoles Using Diformylhydrazine-- New Directions from Academia.
  • (source: Nielsen Book Data)9781782623847 20180213
In recent years, a significant amount of progress has been made using green chemistry in the synthesis of synthetically useful compounds and molecules by replacing hazardous chemicals with greener alternatives. However, there is still room for improvement, especially in the pharmaceutical sector where new drugs are being formulated. This book examines green approaches to overcoming hazardous organic transformations. Summarizing recent developments, the book features a detailed description of some of the high impact active pharmaceutical ingredients that have been developed considering green chemistry approaches. It explores the design, engineering and process development and the calculations to account for waste. The book includes strategies to further advance green approaches in the development of generic pharmaceutical industries and features novel, innovative approaches that promote waste-free organic synthesis. This book is of interest to industrialists working in pharmaceuticals and researchers working in green chemistry.
(source: Nielsen Book Data)9781782623847 20180213
VIII, 324 p. : online resource. Digital: text file; PDF.
  • Bioanalytical concepts for environmental toxicology.- In vitro - in vivo endocrine disruptors.- In vitro - in vivo Genotoxicity.- In vitro - in vivo Carcinogenicity.- In vitro - in vivo Modeling.- Key factor Metabolism.- Biosensing.- Effect directed analysis (EDA).
  • (source: Nielsen Book Data)9783319459066 20171211
This book review series presents current trends in modern biotechnology. The aim is to cover all aspects of this interdisciplinary technology where knowledge, methods and expertise are required from chemistry, biochemistry, microbiology, genetics, chemical engineering and computer science.Volumes are organized topically and provide a comprehensive discussion of developments in the respective field over the past 3-5 years. The series also discusses new discoveries and applications. Special volumes are dedicated to selected topics which focus on new biotechnological products and new processes for their synthesis and purification.In general, special volumes are edited by well-known guest editors. The series editor and publisher will however always be pleased to receive suggestions and supplementary information. Manuscripts are accepted in English.
(source: Nielsen Book Data)9783319459066 20171211
1 online resource
Despite considerable technological advances, the pharmaceutical industry is experiencing a severe innovation deficit, especially in the discovery of new drugs. Innovative Approaches in Drug Discovery: Ethnopharmacology, Systems Biology and Holistic Targeting provides a critical review and analysis of health, disease and medicine, and explores possible reasons behind the present crisis in drug discovery. The authors illustrate the benefits of systems biology and pharmacogenomics approaches, and advocate the expansion from disease-centric discovery to person-centric therapeutics involving holistic, multi-target, whole systems approaches. This book lays a path for reigniting pharmaceutical innovation through a disciplined reemergence of pharmacognosy, embracing open innovation models and collaborative, trusted public-private partnerships. With unprecedented advances made in the development of biomedically-relevant tools and technologies, the need is great and the time is now for a renewed commitment towards expanding the repertoire of medicines.ïŽ By incorporating real-life examples and state-of-the-art reviews, this book provides valuable insights into the discovery and development strategies for professionals, academicians, and students in the pharmaceutical sciences.
1 online resource.
  • Preface ix Companion Website Directions xii 1. Introduction: Basic Concepts 1 1.1 Introduction 1 1.2 Drugs and drug nomenclature 3 1.3 Law of mass action 4 1.4 Ionization 9 1.5 Partition coefficients 12 1.6 Further reading 14 2. Drug Administration and Distribution 15 2.1 Introduction 15 2.2 Drug transfer across biological membranes 16 2.3 Drug administration 22 2.4 Drug distribution 31 2.5 Plasma protein binding 38 2.6 Further reading 43 2.7 References 43 3. Drug Metabolism and Excretion 45 3.1 Introduction 45 3.2 Metabolism 46 3.3 Excretion 58 3.4 Further reading 69 3.5 References 69 4. Single compartment Pharmacokinetic Models 71 4.1 Introduction 72 4.2 Systemic clearance 74 4.3 Intravenous administration 76 4.4 Absorption 79 4.5 Infusions 87 4.6 Multiple doses 90 4.7 Non linear kinetics 94 4.8 Relationship between dose, and onset and duration of effect 98 4.9 Limitations of single compartment models 99 4.10 Further reading 100 4.11 References 100 5. Multiple compartment and Non compartment Pharmacokinetic Models 102 5.1 Multiple compartment models 102 5.2 Non compartmental models 117 5.3 Population pharmacokinetics 121 5.4 Curve fitting and the choice of most appropriate model 122 5.5 Further reading 124 5.6 References 124 6. Kinetics of Metabolism and Excretion 126 6.1 Introduction 126 6.2 Metabolite kinetics 127 6.3 Renal excretion 137 6.4 Excretion in faeces 142 6.5 Further reading 143 6.6 References 144 7. Clearance, Protein Binding and Physiological Modelling 145 7.1 Introduction 145 7.2 Clearance 146 7.3 Physiological modelling 158 7.4 Further reading 161 7.5 References 161 8. Quantitative Pharmacological Relationships 162 8.1 Pharmacokinetics and pharmacodynamics 162 8.2 Concentration effect relationships (dose response curves) 163 8.3 Time dependent models 169 8.4 PK PD modelling 173 8.5 Further reading 177 8.6 References 177 9. Pharmacokinetics of Large Molecules 178 9.1 Introduction 178 9.2 Pharmacokinetics 179 9.3 Plasma kinetics and pharmacodynamics 184 9.4 Examples of particular interest 185 9.5 Further reading 191 9.6 References 191 10. Pharmacogenetics and Pharmacogenomics 192 10.1 Introduction 192 10.2 Methods for the study of pharmacogenetics 193 10.3 N Acetyltransferase 194 10.4 Plasma cholinesterase 197 10.5 Cytochrome P450 polymorphisms 199 10.6 Alcohol dehydrogenase and acetaldehyde dehydrogenase 202 10.7 Thiopurine methyltransferase 202 10.8 Phase 2 enzymes 202 10.9 Transporters 204 10.10 Ethnicity 206 10.11 Pharmacodynamic differences 206 10.12 Personalized medicine 208 10.13 Further reading 209 10.14 References 209 11. Additional Factors Affecting Plasma Concentrations 211 11.1 Introduction 211 11.2 Pharmaceutical factors 213 11.3 Sex 214 11.4 Pregnancy 218 11.5 Weight and obesity 220 11.6 Food, diet and nutrition 225 11.7 Time of day 226 11.8 Posture and exercise 228 11.9 Further reading 231 11.10 References 231 12. Effects of Age and Disease on Drug Disposition 233 12.1 Introduction 233 12.2 Age and development 234 12.3 Effects of disease on drug disposition 242 12.4 Assessing pharmacokinetics in special populations 256 12.5 Further reading 257 12.6 References 258 13. Drug Interactions and Toxicity 260 13.1 Introduction 260 13.2 Drug interactions 261 13.3 Toxicity 273 13.4 Further reading 282 13.5 References 282 14. Perspectives and Prospects: Reflections on the Past, Present and Future of Drug Disposition and Pharmacokinetics 284 14.1 Drug disposition and fate 284 14.2 Pharmacodynamics 286 14.3 Quantification of drugs and pharmacokinetics 286 14.4 The future 289 14.5 Postscript 291 14.6 Further reading 292 14.7 References 292 Appendices 1 Mathematical Concepts and the Trapezoidal Method 293 2 Dye Models to Teach Pharmacokinetics 300 3 Curve Fitting 303 4 Pharmacokinetic Simulations 307 Index 312.
  • (source: Nielsen Book Data)9781119261049 20170403
The application of knowledge of drug disposition, and skills in pharmacokinetics, are crucial to the development of new drugs and to a better understanding of how to achieve maximum benefit from existing ones. The book takes the reader from basic concepts to a point where those who wish to will be able to perform pharmacokinetic calculations and be ready to read more advanced texts and research papers. The book will be of benefit to students of medicine, pharmacy, pharmacology, biomedical sciences and veterinary science, including those who have elected to study the topic in more detail, such as via electives and special study modules. It will be of benefit to those involved in drug discovery and development, pharmaceutical and medicinal chemists, as well as budding toxicologists and forensic scientists who require the appropriate knowledge to interpret their findings and as an introductory text for clinical pharmacologists. Early chapters describe the basic principles of the topic while the later ones illustrate the application of those principles to modern approaches to drug development and clinical use. Full colour illustrations facilitate the learning experience and supporting material for course leaders and students can be found on the Companion Web Site.
(source: Nielsen Book Data)9781119261049 20170403
ix, 701 pages : illustrations ; 28 cm
  • Interpretive tools
  • States of matter
  • Thermodynamics
  • Physical properties determination
  • Nonelectrolytes
  • Electrolyte solutions
  • Ionic equilibria
  • Buffered and isotonic solutions
  • Solubility and distribution phenomena
  • Complexation and protein binding
  • Diffusion
  • Biopharmaceutics
  • Drug release and dissolution
  • Chemical kinetics and stability
  • Interfacial phenomena
  • Rheology
  • Colloidal dispersions & nanotechnology
  • Coarse dispersions
  • Micromeritics
  • Pharmaceutical biotechnology
  • Pharmaceutical polymers
  • Compounding
  • Excipients
  • Oral solid dosage forms
  • Drug delivery systems and drug product design.
Martin's Physical Pharmacy and Pharmaceutical Sciences is considered the most comprehensive text available on the physical, chemical, and biological principles that underlie pharmacology. This 7th Edition puts a stronger focus on the most essential, practical knowledge, and is updated to reflect the broadening scope and diversity of the pharmaceutical sciences. Whether you're a student, teacher, researcher, or industrial pharmaceutical scientist, this respected textbook and reference will help you apply the elements of biology, physics, and chemistry in your work and study. Master the latest knowledge with brand-new chapters on Excipients and Compounding; revised and expanded coverage of interpretive tools, ionic equilibria, biopharmaceutics, diffusion, drug release and dissolution, and drug delivery systems and drug product design; a renewed focus on physical chemistry; and much more. See how physical chemistry principles apply to practice through abundant examples. Focus on the most need-to-know information via Key Concept boxes..
(source: Nielsen Book Data)9781451191455 20170213
Science Library (Li and Ma)
520 pages : 187 b/w images and 187 line drawings ; cm.
  • Foreword Introduction Acanthopanax senticosus Adhatoda vasica Aegle marmelos Alstonia macrophylla Artemisia herba-alba Artemisia capillaris Astilbe rubra Barringtonia racemosa Biophytum sensitivum Broussonetia kazinoki Calamintha officinalis Camellia japonica Camellia sinensis Carissa carandas Carthamus tinctorius Castanea crenata Castanospermum austral Cedrela odorata Centella asiatica Celosia argentea Chlorophytum borivilianum Chromolaena odorata Cichorium intybus Clerodendrum bungei Cnidium officinale Commelina communis Coptis chinensis Cotylelobium melanoxylon Cichorium intybus Dioscorea bulbifera Dolichandrone falcata Dendrobium loddigesii Ducrosia anethifolia Duranta repens Echium vulgare Elephantopus mollis Embelia ribes Euphorbia thymifolia Ficus deltoidea Garcinia cambogia Garcinia mangostana Gardenia jasminoides Gymnema sylvestre Hibiscus sabdariffa Holarrhena antidysenterica Hyssopus officinalis Ipomoea batatas Kochia scoparia Lagenaria siceraria Lagertroemia speciosa Lawsonia inermis Lonicera coerulea Lepidium sativum Ligusticum chuanxiong Lithospermum erythrorhizon Mangifera indica Melissa officinalis Morus alba Mucunia pruriens Murraya koenigii Nelumbo nucifera Neolamarckia cadamba Nigella sativa Ocimum basilicum Olea europea Origanum vulgare Orthosiphon aristatus Panax japonica Peucedanum japonicum Phyllanthus reticulatus Picris hieracioides Piper longum Pistacia chinensis Platycodon grandiflorum Polygala aureocauda Polygonatum odoratum Polygonum cuspidatum Premna tomentosa Pterocarpus marsupium Punica granatum Raphanus raphanistrum Rheum ribes Rosmarinus officinalis Rubia yunnanensis Salacia oblonga Salacia reticulata Salvia miltiorrhiza Salvia officinalis Saururus chinensis Sesamum indicum Scutellaria baicalensis Sorbus commixta Shorea roxburghii Sinocrassula indica Siraitia grosvenorii Silybum marianum Smallanthus sonchifolius Stereospermum colais Swertia chirata Swertia kouitchensis Spilanthes acmella Tamarindus indica Taraxacum officinale Tectona grandis Terminalia bellirica Terminalia superba Tinosporora cordifolia Trapa japonica Tussilago farfara Viscum album Trigonella foenum-graecum Uncaria laevigata Vaccinium myrtillus Viburnum dilatatum Zanthoxylum piperitum Zingiber officinale Index.
  • (source: Nielsen Book Data)9781351711340 20171218
Medicinal Plants in Asia for Metabolic Syndrome: Natural Products and Molecular Basis offers an in-depth view into the metabolic syndrome pharmacology of natural products with an emphasis on their molecular basis, cellular pathways, metabolic organs, and endocrine regulations. This sensational volume provides the scientific names, botanical classifications, botanical descriptions, medicinal uses, chemical constituents, and pharmacological activities of more than 100 Asian plants, with high quality original botanical plates, chemical structures, and pharmacological diagrams. It also lists hundreds of carefully selected bibliographical references, constituents on insulin resistance, obesity, atherosclerosis, atherogenic dyslipidemia, and endothelial dysfunction.
(source: Nielsen Book Data)9781351711340 20171218
1 online resource
  • 1. Selective Effects of Azelaic Acid in Nanovesicles on Cell Lines 2. Photodynamic Antimicrobial Action Based on Nanostructured Photosensitizers 3. Conspectus on Nanotechnology in the Diagnosis and Management of Oral Cancer 4. Lipid-Based Nanocarriers in Cancer Therapy 5. Effect of Polymer-Based Nanoparticles on the Assay of Antimicrobial Drug Delivery Systems 6. Nanometric Biopolymer Devices for Oral Delivery of Macromolecules of Clinical Significance 7. The Use of Nanotechnology in Modern Pharmacotherapy 8. Nanoparticles for Anti-Cancer Drug Delivery "Targeting to Overcome Multiple Drug Resistance" 9. Application Potential of Engineered Liposomes in Tumor Targeting 10. Plant Based Peroral Vaccines 11. Platelet Rich Plasma Incorporated Nanostructures for Tissue Engineering Applications 12. Targeted Nanotherapeutics Based on Cancer Biomarkers 13. Therapeutic Nanoparticles for Targeted Delivery of Anticancer Drugs: State-Of-The-Art and Future Trends 14. Pulmonary Administration of Biodegradable Drug Nanocarriers for More Efficacious Treatment of Fungal Infections in Lungs: Insights Based On Recent Findings 15. Alternative Technologies to Improve Solubility of Ineffectively Water-Soluble Drugs 16. Nanostructures For Tuberculosis Disease Treatment 17. Recombinant Lactic Acid Bacteria Secreting OxdC as a Novel Therapeutic Tool for the Prevention of Kidney Stone Disease.
  • (source: Nielsen Book Data)9780323527255 20170612
Multifunctional Systems for Combined Delivery, Biosensing, and Diagnostics explores how multifunctional nanocarriers are being used in combined delivery and diagnostics in contemporary medicine. Particular attention is given to efforts to i) reduce the side effects of therapeutic agents, ii) increase the pharmacological effect, and iii) improve aqueous solubility and chemical stability of different therapeutic agents. The chapters focus on applications of nanostructured materials and nanocarriers, highlighting how these can be used effectively in both diagnosis and delivery. This applied focus makes the book an important reference source for those wanting to learn more about how specific nanomaterials and nanotechnology systems can help to solve drug delivery and diagnostics problems. This book is a valuable resource for materials scientists, bioengineers, and medical researchers who are looking for an applications-oriented guide on how nanotechnology and nanomaterials can be used effectively throughout the medical treatment process, from diagnosis to treatment.
(source: Nielsen Book Data)9780323527255 20170612
XVI, 310 p. 50 ill., 30 illus. in color : online resource. Digital: text file; PDF.
  • 4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins .- Silaproline, a silicon-containing proline surrogate .- Proline Methanologues - Design, Synthesis, Structural Properties, and Applications in Medicinal Chemistry.- Structure and Synthesis of Conformationally Constrained Molecules Containing Piperazic Acid.- Aminolactam, N-aminoimidazolone and N-aminoimdazolidinone peptide mimics.- Azepinone-Constrained Amino Acids in Peptide and Peptidomimetic Design.- Polyhydroxylated cyclic delta amino acids: Synthesis and conformational influences on biopolymers.- Thiazoles in Peptides and Peptidomimetics.- Advances in Merging Triazoles with Peptides and Proteins.
  • (source: Nielsen Book Data)9783319491172 20171211
The series Topics in Heterocyclic Chemistry presents critical reviews on present and future trends in the research of heterocyclic compounds. Overall the scope is to cover topics dealing with all areas within heterocyclic chemistry, both experimental and theoretical, of interest to the general heterocyclic chemistry community. The series consists of topic related volumes edited by renowned editors with contributions of experts in the field. All chapters from Topics in Heterocyclic Chemistry are published Online First with an individual DOI. In references, Topics in Heterocyclic Chemistry is abbreviated as Top Heterocycl Chem and cited as a journal.
(source: Nielsen Book Data)9783319491172 20171211
XIII, 256 p. : online resource. Digital: text file; PDF.
  • Oligooxopiperazines as Topographical Helix Mimetics.- Heterocyclic Extended Peptide Surrogates for ss-Strand Stabilization.- Diketopiperazine based peptide mimic scaffolds.- Synthesis of Constrained Peptidomimetics via the Pictet-Spengler Reaction.- Peptidomimetics via Iminium Ion Chemistry on Solid Phase: Single, Fused, and Bridged Heterocycles.- Synthesis of peptidomimetics through the disrupted Ugi reaction with aziridine aldehyde dimers.- Some Recent Studies on Gramicidin S Analogs, Their Structures and Antimicrobial Activities.- Anti-amyloidogenic Heterocyclic Peptides.- Lipoylated peptides and proteins.
  • (source: Nielsen Book Data)9783319491233 20171211
The series Topics in Heterocyclic Chemistry presents critical reviews on present and future trends in the research of heterocyclic compounds. Overall the scope is to cover topics dealing with all areas within heterocyclic chemistry, both experimental and theoretical, of interest to the general heterocyclic chemistry community. The series consists of topic related volumes edited by renowned editors with contributions of experts in the field. All chapters from Topics in Heterocyclic Chemistry are published Online First with an individual DOI. In references, Topics in Heterocyclic Chemistry is abbreviated as Top Heterocycl Chem and cited as a journal.
(source: Nielsen Book Data)9783319491233 20171211
1 online resource.
  • Foreword xiii Introduction xv About the Contributors xix Part I Challenges Specific to Macrocycles 1 1 Contemporary Macrocyclization Technologies 3Serge Zaretsky and Andrei K. Yudin 1.1 Introduction 3 1.2 Challenges Inherent to the Synthesis of Macrocycles 3 1.3 Challenges in Macrocycle Characterization 6 1.4 Macrocyclization Methods 8 1.5 Cyclization on the Solid Phase 14 1.6 Summary 17 References 18 2 A Practical Guide to Structural Aspects of Macrocycles (NMR, X ]Ray, and Modeling) 25David J. Craik, Quentin Kaas and Conan K. Wang 2.1 Background 25 2.2 Experimental Studies of Macrocycles 31 2.3 Molecular Modeling of Macrocyclic Peptides 38 2.4 Summary 46 Acknowledgments 47 References 47 3 Designing Orally Bioavailable Peptide and Peptoid Macrocycles 59David A. Price, Alan M. Mathiowetz and Spiros Liras 3.1 Introduction 59 3.2 Improving Peptide Plasma Half ]Life 60 3.3 Absorption, Bioavailability, and Methods for Predicting Absorption 61 3.4 In Silico Modeling 70 3.5 Future Directions 71 References 72 Part II Classes of Macrocycles and Their Potential for Drug Discovery 77 4 Natural and Nature ]Inspired Macrocycles: A Chemoinformatic Overview and Relevant Examples 79Ludger A. Wessjohann, Richard Bartelt and Wolfgang Brandt 4.1 Introduction to Natural Macrocycles as Drugs and Drug Leads 79 4.2 Biosynthetic Pathways, Natural Role, and Biotechnological Access 79 4.3 QSAR and Chemoinformatic Analyses of Common Features 84 4.4 Case Studies: Selected Natural Macrocycles of Special Relevance in Medicinal Chemistry 88 References 91 5 Bioactive and Membrane ]Permeable Cyclic Peptide Natural Products 101Andrew T. Bockus and R. Scott Lokey 5.1 Introduction 101 5.2 Structural Motifs and Permeability of Cyclic Peptide Natural Products 101 5.3 Conformations of Passively Permeable Bioactive Cyclic Peptide Natural Products 103 5.4 Recently Discovered Bioactive Cyclic Peptide Natural Products 108 5.5 Conclusions 125 References 125 6 Chemical Approaches to Macrocycle Libraries 133Ziqing Qian, Patrick G. Dougherty and Dehua Pei 6.1 Introduction 133 6.2 Challenges Associated with Macrocyclic One ]Bead ]One-Compound Libraries 134 6.3 Deconvolution of Macrocyclic Libraries 134 6.4 Peptide ]Encoded Macrocyclic Libraries 136 6.5 DNA ] Encoded Macrocyclic Libraries 142 6.6 Parallel Synthesis of Macrocyclic Libraries 142 6.7 Diversity ] Oriented Synthesis 145 6.8 Perspective 147 6.9 Conclusion 149 References 150 7 Biological and Hybrid Biological/Chemical Strategies in Diversity Generation of Peptidic Macrocycles 155Francesca Vitali and Rudi Fasan 7.1 Introduction 155 7.2 Cyclic Peptide Libraries on Phage Particles 155 7.3 Macrocyclic Peptide Libraries via In Vitro Translation 166 7.4 Emerging Strategies for the Combinatorial Synthesis of Hybrid Macrocycles In Vitro and in Cells 171 7.5 Comparative Analysis of Technologies 175 7.6 Conclusions 178 References 178 8 Macrocycles for Protein Protein Interactions 185Eilidh Leitch and Ali Tavassoli 8.1 Introduction 185 8.2 Library Approaches to Macrocyclic PPI Inhibitors 186 8.3 Structural Mimicry 192 8.4 Multi ] Cycles for PPIs 197 8.5 The Future for Targeting PPIs with Macrocycles 197 References 200 Part III The Synthetic Toolbox for Macrocycles 205 9 Synthetic Strategies for Macrocyclic Peptides 207Eric Biron, Simon Vezina ]Dawod and Francois Bedard 9.1 Introduction to Peptide Macrocyclization 207 9.2 One Size Does Not Fit All: Factors to Consider During Synthesis Design 209 9.3 Peptide Macrocyclization in Solution 213 9.4 Peptide Macrocyclization on Solid Support 220 9.5 Peptide Macrocyclization by Disulfide Bond Formation 226 9.6 Conclusion 229 References 230 10 Ring ]Closing Metathesis ]Based Methods in Chemical Biology: Building a Natural Product Inspired Macrocyclic Toolbox to Tackle Protein Protein Interactions 243Jagan Gaddam, Naveen Kumar Mallurwar, Saidulu Konda, Mahender Khatravath, Madhu Aeluri, Prasenjit Mitra and Prabhat Arya 10.1 Introduction 243 10.2 Protein Protein Interactions: Challenges and Opportunities 243 10.3 Natural Products as Modulators of Protein Protein Interactions 243 10.4 Introduction to Ring ]Closing Metathesis 244 10.5 Selected Examples of Synthetic Macrocyclic Probes Using RCM ]Based Approaches 246 10.6 Summary 259 References 259 11 The Synthesis of Peptide-Based Macrocycles by Huisgen Cycloaddition 265Ashok D. Pehere and Andrew D. Abell 11.1 Introduction 265 11.2 Dipolar Cycloaddition Reactions 266 11.3 Macrocyclic Peptidomimetics 267 11.4 Macrocyclic ]Strand Mimetics as Cysteine Protease Inhibitors 273 11.5 Conclusion 275 References 277 12 Palladium ]Catalyzed Synthesis of Macrocycles 281Thomas O. Ronson, William P. Unsworth and Ian J. S. Fairlamb 12.1 Introduction 281 12.2 Stille Reaction 281 12.3 Suzuki Miyaura Reaction 285 12.4 Heck Reaction 288 12.5 Sonogashira Reaction 290 12.6 Tsuji Trost Reaction 293 12.7 Other Reactions 295 12.8 Conclusion 298 References 298 13 Alternative Strategies for the Construction of Macrocycles 307Jeffrey Santandrea, Anne ]Catherine Bedard, Mylene de Leseleuc, Michael Raymond and Shawn K. Collins 13.1 Introduction 307 13.2 Alternative Methods for Macrocyclization Involving Carbon Carbon Bond Formation 307 13.3 Alternative Methods for Macrocyclization Involving Carbon Carbon Bond Formation: Ring Expansion and Photochemical Methods 320 13.4 Alternative Methods for Macrocyclization Involving Carbon Oxygen Bond Formation 322 13.5 Alternative Methods for Macrocyclization Involving Carbon Nitrogen Bond Formation 327 13.6 Alternative Methods for Macrocyclization Involving Carbon Sulfur Bond Formation 328 13.7 Conclusion and Summary 331 References 332 14 Macrocycles from Multicomponent Reactions 339Ludger A. Wessjohann, Ricardo A. W. Neves Filho, Alfredo R. Puentes and Micjel Chavez Morejon 14.1 Introduction 339 14.2 General Aspects of Multicomponent Reactions (MCRs) in Macrocycle Syntheses 344 14.3 Concluding Remarks and Future Perspectives 369 References 371 15 Synthetic Approaches Used in the Scale ]Up of Macrocyclic Clinical Candidates 377Jongrock Kong 15.1 Introduction 377 15.2 Background 377 15.3 Literature Examples 378 15.4 Conclusions 406 References 406 Part IV Macrocycles in Drug Development: Case Studies 411 16 Overview of Macrocycles in Clinical Development and Clinically Used 413Silvia Stotani and Fabrizio Giordanetto 16.1 Introduction 413 16.2 Datasets Generation 413 16.3 Marketed Macrocyclic Drugs 414 16.4 Macrocycles in Clinical Studies 422 16.5 De Novo Designed Macrocycles 429 16.6 Overview and Conclusions 436 Appendix 16.A 437 16.A.1 Methods 437 References 490 17 The Discovery of Macrocyclic IAP Inhibitors for the Treatment of Cancer 501Nicholas K. Terrett 17.1 Introduction 501 17.2 DNA ]Programmed Chemistry Macrocycle Libraries 502 17.3 A New Macrocycle Ring Structure 504 17.4 Design and Profiling of Bivalent Macrocycles 506 17.5 Improving the Profile of the Bivalent Macrocycles 510 17.6 Selection of the Optimal Bivalent Macrocyclic IAP Antagonist 512 17.7 Summary 515 Acknowledgments 515 References 516 18 Discovery and Pharmacokinetic Pharmacodynamic Evaluation of an Orally Available Novel Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase and c ]Ros Oncogene 1 519Shinji Yamazaki, Justine L. Lam and Ted W. Johnson 18.1 Introduction 519 18.2 Discovery and Synthesis 520 18.3 Evaluation of Pharmacokinetic Properties Including CNS Penetration 531 18.4 Evaluation of Pharmacokinetic Pharmacodynamic (PKPD) Profiles 536 18.5 Conclusion 540 References 540 19 Optimization of a Macrocyclic Ghrelin Receptor Agonist (Part II): Development of TZP ]102 545Hamid R. Hoveyda, Graeme L. Fraser, Eric Marsault, Rene Gagnon and Mark L. Peterson 19.1 Introduction 545 19.2 Advanced AA3 and Tether SAR 548 19.3 Structural Studies 554 19.4 Conclusions 554 Acknowledgments 555 References 556 20 Solithromycin: Fourth ]Generation Macrolide Antibiotic 559David Pereira, Sara Wu, Shingai Majuru, Stephen E. Schneider and Lovy Pradeep 20.1 Introduction 559 20.2 Structure Activity Relationship (SAR) of Ketolides and Selection of Solithromycin 559 20.3 Mechanism of Action 564 20.4 Overcoming the Ketek Effect 568 20.5 Manufacture of Solithromycin 569 20.6 Polymorphism 569 20.7 Pharmaceutical Development 569 20.8 Clinical Data 574 20.9 Summary 574 References 574 Index 579.
  • (source: Nielsen Book Data)9781119092568 20171211
Including case studies of macrocyclic marketed drugs and macrocycles in drug development, this book helps medicinal chemists deal with the synthetic and conceptual challenges of macrocycles in drug discovery efforts. Provides needed background to build a program in macrocycle drug discovery design criteria, macrocycle profiles, applications, and limitationsFeatures chapters contributed from leading international figures involved in macrocyclic drug discovery effortsCovers design criteria, typical profile of current macrocycles, applications, and limitations.
(source: Nielsen Book Data)9781119092568 20171211
1 online resource ( v, 246 pages) : illustrations (some color).
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  • Xanthine Alkaloids: Occurrence, Biosynthesis, and Function in Plants; 1 Introduction; 2 Occurrence of Xanthine Alkaloids in the Plant Kingdom; 2.1 Ericales (Tea and Related Species); 2.2 Gentianales (Coffee and Related Species); 2.3 Aquifoliales (Maté and Related Species); 2.4 Malvales (Cacao, Cola, and Related Species); 2.5 Sapindales (Guaran, Citrus, and Related Plants); 2.6 Other Species; 3 Biosynthesis of Xanthine Alkaloids; 3.1 A Brief History of the Elucidation of the Biosynthesis Pathways; 3.2 Caffeine Biosynthesis Pathways from Xanthosine; 3.2.1 Formation of 7-Methylxanthine
  • Feeding ExperimentsEnzyme Studies; Genes and Proteins; 3.2.2 Conversion of 7-Methylxanthine to Caffeine via Theobromine; Feeding Experiments; Enzyme Studies; Genes and Proteins; 3.2.3 Evolutionary Relationship of the Caffeine Synthase Family Proteins; 3.3 Pathways that Supply Xanthosine for Caffeine Biosynthesis; 3.3.1 De Novo Route; 3.3.2 AMP Route; 3.3.3 SAM Cycle Route; 3.3.4 NAD Route; 3.3.5 GMP Route; 3.4 Localization of Xanthine Alkaloid Biosynthesis; 3.4.1 Organs and Tissues; Camellia; Coffea; Theobroma; Maté and Guaran; 3.4.2 Subcellular Accumulation of Xanthine Alkaloids
  • 3.4.3 Subcellular Localization of Caffeine Biosynthesis EnzymesCaffeine Synthase; Enzymes Involved in the de Novo Route; Enzymes Involved in the AMP Route; Enzymes Involved in the SAM Route; 3.4.4 Subcellular Localization and Transport of Intermediates; 3.5 Regulation of Caffeine Biosynthesis; 4 Metabolism of Xanthine Alkaloids; 4.1 Methyluric Acid Biosynthesis; 4.2 Biodegradation and Inter-conversion of Xanthine Alkaloids; 4.2.1 The Major Pathway of Caffeine Degradation; 4.2.2 Conventional Purine Catabolic Pathways in Plants; 4.2.3 Diversity of Xanthine Alkaloid Metabolism in Plants; Coffea
  • Tea4.2.4 Xanthine Alkaloid Metabolism in Bacteria and Animals; Bacteria; Animals; 5 Ecological Roles of Xanthine Alkaloids; 5.1 Allelopathic Function Theory; 5.1.1 Effect of Xanthine Alkaloids on Germination and Growth of Plants; 5.1.2 Effect of Xanthine Alkaloids on Proliferation of Plant Cells; 5.1.3 Effect of Xanthine Alkaloids on Plant Metabolism; 5.1.4 Effect of Caffeine on Protein Expression Profiles; 5.1.5 Allelopathy in Natural Ecosystems; 5.2 Chemical Defense Theory; 5.2.1 Chemical Defense Against Microorganisms and Animals
  • 5.2.2 Proof of the Chemical Defense Theory Demonstrated with Transgenic Plants6 Biotechnology of Xanthine Alkaloids; 6.1 Decaffeinated Coffee and Tea Plants; 6.2 Caffeine-Producing Transgenic Plants; 6.2.1 Antiherbivore Activity; 6.2.2 Antipathogen Activity; 7 Summary and Perspectives; References; The Iboga Alkaloids; 1 Introduction; 2 Biosynthesis; 3 Structural Elucidation and Reactivity; 4 New Molecules; 4.1 Monomers; 4.1.1 Ibogamine and Coronaridine Derivatives; 4.1.2 3-Alkyl- or 3-Oxo-ibogamine/-coronaridine Derivatives; 4.1.3 5- and/or 6-Oxo-ibogamine/-coronaridine Derivatives
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  • Chapter 1. Traditional Chinese Medicine: Current State, Challenges, and Applications Chapter 2. Serum Pharmacochemistry of Traditional Chinese Medicine: Historical Development and Strategies Chapter 3. Integrated Serum Pharmacochemistry of TCM and Metabolomics Strategies for Innovative Drug Discovery Chapter 4. UPLC/MS and Its Potential in Traditional Chinese Medicine Development Chapter 5. Analytical Characterization of Yin-Chen-Hao-Tang by Serum Pharmacochemistry of TCM Chapter 6. Pharmacokinetic Strategy for Screening the Effective Components From YCHT Chapter 7. Synergism Effects of Active Ingredients From YCHT Chapter 8. Serum Pharmacochemistry of TCM for Screening the Active Ingredients From Wen-Xin Formulae Chapter 9. Characterization and Pharmacokinetic Study of Multiple Constituents From Shengmai San Chapter 10. Multivariate Data Processing Tools to Screen the Active Ingredients From Kai-Xin-San Chapter 11. Serum Pharmacochemistry of TCM for Determining the Active Ingredients of Shuanghuanglian Formulae Chapter 12. Pharmacokinetic-Pharmacodynamic Study of Zhi Zhu Wan Chapter 13. Identification of the Absorbed Components of Shaoyao-Gancao Decoction Chapter 14. Rapid Analysis of Multiple Constituents of Suanzaoren Decoction by UPLC-MS Chapter 15. UPLC-MS Analysis of the Chemical Constituents of Liuwei Dihuang Wan Chapter 16. Multivariate Data Analysis for Rapid Identification of Chemical Constituents of Simiao Wan Chapter 17. Time-Course Study of Multicomponents After Oral Administration of Stemonae Radix Chapter 18. Global Characterization of Chemical Constituents of Phellodendri amurensis Cortex Chapter 19. Comparative Analysis of Chemical Constituents of Phellodendri amurensis Cortex and Zhibai Dihuang Pill Chapter 20. UPLC-MS Determining the Active Ingredients of Herbal Fructus Corni In Vivo Chapter 21. Serum Pharmacochemistry of TCM Screening the Bioactive Components From Moutan Cortex Chapter 22. Rapid Analysis of Constituents and Metabolites From Extracts of Acanthopanax senticosus Harms Leaf Chapter 23. Systematic Characterization of the Absorbed Components of Acanthopanax senticosus Stem Chapter 24. Identification of the Absorbed Constituents of Schisandra Lignans by Serum Pharmacochemistry of TCM.
  • (source: Nielsen Book Data)9780128111475 20170313
Serum Pharmacochemistry of Traditional Chinese Medicine: Technologies, Strategies and Applications provides a valuable and indispensable guide on the latest methods, research advances, and applications in this area. Chapters offer cutting-edge information on pharmacokinetics and pharmacodynamics, analytical chemistry, traditional medicine, natural products, bioinformatics, new technologies, therapeutic applications, and more. For researchers and students in academia and industry, this book provides a hands-on description of experimental techniques, along with beneficial guidelines to help advance research in the fields of Traditional Chinese Medicine and drug development.
(source: Nielsen Book Data)9780128111475 20170313
1 online resource
  • Preface XIII List of Contributors XVII Part I HDAC Inhibitor Anticancer Drug Discovery 1 1 From DMSO to the Anticancer Compound SAHA, an Unusual Intellectual Pathway for Drug Design 3Ronald Breslow 1.1 Introduction 3 1.2 The Discovery of SAHA (vorinostat) 4 1.3 Clinical Trials 7 1.4 Follow-On Research - Selective HDAC Inhibitors 8 1.5 Conclusion 9 References 9 2 Romidepsin and the Zinc-Binding Thiol Family of Natural Product HDAC Inhibitors 13A. Ganesan 2.1 Histone Deacetylases as a Therapeutic Target 13 2.2 The Discovery and Development of Romidepsin 15 2.3 The Zinc-BindingThiol Family of Natural Product HDAC Inhibitors 18 2.4 Synthetic Analogues of the Zinc-BindingThiol Natural Products 21 2.5 Summary 23 References 24 3 The Discovery and Development of Belinostat 31Paul W. Finn, Einars Loza and Elisabeth Carstensen 3.1 Introduction 31 3.2 Discovery of Belinostat 32 3.2.1 Design Strategy 32 3.2.2 Medicinal Chemistry and SAR 34 3.3 Belinostat Biological Profiling 41 3.3.1 Mode of Action and HDAC Isoform Selectivity 41 3.3.2 Antiproliferative and Antitumor Activity 42 3.4 Formulation Development 44 3.5 Clinical Development 45 3.5.1 Clinical Studies Leading to Approval and Other Clinical Investigations 45 3.5.2 Pharmacokinetics 49 3.5.3 Safety and Tolerability 51 3.6 Conclusions 52 References 53 4 Discovery and Development of Farydak (NVP-LBH589, Panobinostat) as an Anticancer Drug 59Peter Atadja and Lawrence Perez 4.1 Target Identification: From p21Waf1 Induction to HDAC Inhibition 59 4.2 Program Flowchart Assays for Drug Discovery 61 4.3 Hit-To-Lead Campaign: Trichostatin A to LAK974 63 4.4 Lead Optimization: LAK974 to LAQ824 64 4.5 Profiling LAQ824 for Cancer Therapy 66 4.6 Preclinical Development of LAQ824 70 4.7 LAQ824 Follow-Up 72 4.8 Discovery of LBH589 73 4.9 Safety Profile for LBH589 74 4.10 Pan-HDAC Inhibition by LBH589 76 4.11 Cancer Cell-Specific Cytotoxicity of LBH589 76 4.11.1 Toxicity and Safety Studies with LBH589 78 4.11.2 Early Clinical Activity of LBH589 in CTCL 78 4.11.3 Large-Scale Cell Line Profiling to Discover Lineage-Specific LBH589-Sensitive Cancer Indications 79 4.11.4 Clinical Profiling ofHemeMalignancies for LBH589Activity 80 4.11.5 Phase II Study of Oral Panobinostat in Hodgkin Lymphoma 81 4.11.6 Phase IB Clinical Studies in MultipleMyeloma 82 4.11.7 Phase III Registration Study inRelapsed orRefractoryMyeloma 82 4.11.8 Conclusion and Future Perspective 83 References 85 5 Discovery and Development of HDAC Subtype Selective Inhibitor Chidamide: Potential Immunomodulatory Activity Against Cancers 89Xian-Ping Lu, Zhi-Qiang Ning, Zhi-Bin Li, De-Si Pan, Song Shan, Xia Guo, Hai-Xiang Cao, Jin-Di Yu and Qian-Jiao Yang 5.1 Introduction 89 5.1.1 Epigenetics and Cancer 89 5.1.2 Epigenetic Drugs 90 5.2 Discovery of Chidamide 93 5.2.1 Identification of Chemical Scaffold 93 5.2.2 Design and ScreeningNewSelective BenzamideHDACInhibitors 93 5.2.3 Molecular Docking of Chidamide with HDAC2 95 5.3 Molecular Mechanisms of Chidamide 97 5.3.1 Selectivity 97 5.3.2 Induction of Cell Cycle Arrest, Apoptosis and Differentiation of Tumour Cells 98 5.3.3 Reversal of Epithelial toMesenchymal Transition 99 5.3.4 Stimulation of Innate andAntigen-SpecificAntitumour Immunity 99 5.3.5 Multiplicity of Anticancer Mechanisms by Chidamide 100 5.4 Animal Studies 101 5.5 Clinical Development 101 5.5.1 Pharmacokinetics and Pharmacodynamics 101 5.5.2 Unmet Medical Needs for PeripheralT-Cell Lymphoma (PTCL) 102 5.5.3 Efficacy Assessment of Chidamide in PTCL Patients 103 5.5.4 Safety Profile 105 5.6 Future Perspective 106 References 108 Part II Steroidal CYP17 Inhibitor Anticancer Drug Discovery 115 6 Abiraterone Acetate (Zytiga): AnInhibitor of CYP17 as a Therapeutic for Castration-Resistant Prostate Cancer 117Gabriel M. Belfort, Boyd L. Harrisonand Gabriel Martinez Botella 6.1 Introduction 117 6.2 Discovery and Structure-Activity Relationships (SAR) 119 6.3 Preclinical Characterisation of Abiraterone and Abiraterone Acetate 126 6.3.1 Pharmacology 126 6.3.2 Pharmacokinetics 127 6.3.3 Toxicology 128 6.4 Physical Characterisation 129 6.5 Clinical Studies 129 6.6 Conclusion 132 References 133 Part III Anti-Infective Drug Discoveries 137 7 Discovery of Delamanid for the Treatment of Multidrug-Resistant Pulmonary Tuberculosis 139Hidetsugu Tsubouchi, Hirofumi Sasaki, Hiroshi Ishikawa and Makoto Matsumoto 7.1 Introduction 139 7.2 Synthesis Strategy 140 7.3 Synthesis Route 142 7.4 Screening Evaluations 145 7.4.1 Screening Procedure 145 7.4.2 Screening Results 146 7.4.3 Selection of a Compound Candidate for Preclinical Tests 151 7.5 Preclinical Data of Delamanid 151 7.5.1 Antituberculosis Activity 151 7.5.2 Mechanism of Action 153 7.5.3 Pharmacokinetics 153 7.5.4 Genotoxicity and Carcinogenicity 154 7.5.5 Preclinical Therapeutic Efficacy 154 7.6 Clinical Data of Delamanid 155 7.6.1 Clinical Pharmacokinetics 155 7.6.2 Drug-Drug Interactions 156 7.6.3 Cardiovascular Safety 156 7.6.4 Clinical Therapeutic Efficacy 156 7.6.5 Other Clinical Trials 157 7.7 Future Priorities and Conclusion 158 References 159 8 Sofosbuvir: The Discovery of a Curative Therapy for the Treatment of Hepatitis C Virus 163Michael J. Sofia 8.1 Introduction 163 8.2 Discussion 165 8.2.1 Target Rationale: HCVNS5BRNA-Dependent RNA Polymerase 165 8.2.2 Rationale andDesign of a Liver Targeted Nucleotide Prodrug 168 8.2.3 Prodrug Optimization and Preclinical Evaluation 171 8.2.4 Prodrug Metabolism 175 8.2.5 Clinical Proof of Concept of a Liver Targeted Nucleotide Prodrug 176 8.2.6 The Single Diastereomer: Sofosbuvir 176 8.2.7 Sofosbuvir Preclinical Profile 177 8.2.8 Sofosbuvir Clinical Studies 179 8.2.9 Viral Resistance 182 8.3 Conclusion 183 References 184 Part IV Central Nervous System (CNS) Drug Discovery 189 9 The Discovery of the Antidepressant Vortioxetine and the Research that Uncovered Its Potential to Treat the Cognitive Dysfunction Associated with Depression 191Benny Bang-Andersen, Christina Kurre Olsen and Connie Sanchez 9.1 Introduction 191 9.2 The Discovery of Vortioxetine 192 9.3 Clinical Development of Vortioxetine for theTreatment ofMDD 200 9.4 UncoveringVortioxetine's Potential toTreat Cognitive Dysfunction in Patients with MDD 201 9.4.1 Early Preclinical Evidence that Differentiated Vortioxetine from Other Antidepressants 201 9.4.2 Vortioxetine's Primary Targets and Their Putative Impact on Cognitive Function - Early Preclinical Data 202 9.4.3 Hypothesis-Generating Clinical Study of Vortioxetine's Effects on Cognitive Symptoms in Elderly Patients with MDD 203 9.4.4 Substantiation of a Mechanistic Rationale for the Procognitive Effects of Vortioxetine in Preclinical Models and Its Differentiation from SSRIs and SNRIs 204 9.4.5 Confirmation of the Cognitive Benefits of Vortioxetine in Two Large Placebo-Controlled Studies in Adults with MDD 205 9.4.6 Additional Translational Evidence of the Effect of Vortioxetine on Brain Activity During Cognitive Performance 208 9.5 Conclusion 208 References 210 Part V Antiulcer Drug Discovery 215 10 Discovery of Vonoprazan Fumarate (TAK-438) as a Novel, Potent and Long-Lasting Potassium-Competitive Acid Blocker 217Haruyuki Nishida 10.1 Introduction 217 10.2 Limitations of PPIs and the Possibility of P-CABs 218 10.3 Exploration of Seed Compounds 220 10.4 Lead Generation from HTS Hit Compound 1 220 10.5 Analysis of SAR and Structure-Toxicity Relationship for Lead Optimization 223 10.6 Selection of Vonoprazan Fumarate (TAK-438) as a Candidate Compound 224 10.7 Preclinical Study of TAK-438 226 10.8 Clinical Study of TAK-438 228 10.9 Discussion 229 10.10 Conclusion 230 References 232 Part VI Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anticancer) 235 11 Discovery and Development of Nintedanib: A Novel Antiangiogenic and Antifibrotic Agent 237Gerald J. Roth, Rudolf Binder, Florian Colbatzky, Claudia Dallinger, Rozsa Schlenker-Herceg, Frank Hilberg, Lutz Wollin, John Park, Alexander Pautsch and Rolf Kaiser 11.1 Introduction 237 11.2 Structure-Activity Relationships of Oxindole Kinase Inhibitors and the Discovery of Nintedanib 238 11.3 Structural Research 244 11.4 Preclinical Pharmacodynamic Exploration 246 11.4.1 Kinase Inhibition Profile of Nintedanib 246 11.4.2 Oncology, Disease Pathogenesis and Mechanism of Action 246 11.4.3 Idiopathic Pulmonary Fibrosis, Disease Pathogenesis andMechanism of Action 249 11.5 Nonclinical Drug Metabolism and Pharmacokinetics 250 11.6 Clinical Pharmacokinetics 251 11.7 Toxicology 252 11.8 Phase III Clinical Data 253 11.8.1 Efficacy and Safety of Nintedanib in IPF 253 11.8.2 Efficacy and Safety of Nintedanib in NSCLC 255 11.9 Other Oncology Studies 256 11.10 Conclusions 257 References 258 Index 267.
  • (source: Nielsen Book Data)9783527800346 20170313
  • PART I. HDAC Inhibitor Anticancer Drug Discovery FROM DMSO TO THE ANTICANCER COMPOUND SAHA, AN UNUSUAL INTELLECTUAL PATHWAY FOR DRUG DESIGN Introduction The Discovery of SAHA (vorinostat) Clinical Trials Follow-On Research - Selective HDAC Inhibitors Conclusion ROMIDEPSIN AND THE ZINC-BINDING THIOL FAMILY OF NATURAL PRODUCT HDAC INHIBITORS Histone Deacetylases as a Therapeutic Target The Discovery and Development of Romidepsin The Zinc-Binding Thiol Family of Natural Product HDAC Inhibitors Synthetic Analogues of the Zinc-Binding Thiol Natural Products Summary THE DISCOVERY AND DEVELOPMENT OF BELINOSTAT Introduction Discovery of Belinostat Belinostat Biological Profiling Formulation Development Clinical Development Conclusions DISCOVERY AND DEVELOPMENT OF FARYDAK (NVP-LBH589, PANOBINOSTAT) AS AN ANTICANCER DRUG Target Identification: From p21Wafl Induction to HDAC Inhibition Program Flowchart Assays for Drug Discovery Hit-To-Lead Campaign: Trichostatin A to LAK974 Lead Optimization: LAK974 to LAQ824 Profiling LAQ824 for Cancer Therapy Preclinical Development of LAQ824 LAQ824 Follow-Up Discovery of LBH589 Safety Profile for LBH589 Pan-HDAC Inhibition by LBH589 Cancer Cell-Specific Cytotoxicity of LBH589 DISCOVERY AND DEVELOPMENT OF HDAC SUBTYPE SELECTIVE INHIBITOR CHIDAMIDE: POTENTIAL IMMUNOMODULATORY ACTIVITY AGAINST CANCER Introduction Discovery of Chidamide Molecular Mechanisms of Chidamide Animal Studies Clinical Development Future Perspective PART II. Steroidal CYP17 Inhibitor Anticancer Drug Discovery ABIRATERONE ACETATE (ZYTIGA): AN INHIBITOR OF CYP17 AS A THERAPEUTIC FOR CASTRATION-RESISTANT PROSTATE CANCER Introduction Discovery and Structure-Activity Relationships (SAR) Preclinical Characterisation of Abiraterone Physical Characterisation Clinical Studies Conclusion PART III. Anti-Infective Drug Discoveries DISCOVERY OF DELAMANID FOR THE TREATMENT OF MULTIDRUG-RESISTANT PULMONARY TUBERCULOSIS Introduction Synthesis Strategy Synthesis Route Screening Evaluations Preclinical Data of Delamanid Clinical Data of Delamanid Future Priorities and Conclusion SOFOSBUVIR: THE DISCOVERY OF A CURATIVE THERAPY FOR THE TREATMENT OF HEPATITIS C VIRUS Introduction Discussion Conclusion PART IV. Central Nervous System (CNS) Drug Discovery THE DISCOVERY OF THE ANTIDEPRESSANT VORTIOXETINE AND THE RESEARCH THAT UNCOVERED ITS POTENTIAL TO TREAT THE COGNITIVE DYSFUNCTION ASSOCIATED WITH DEPRESSION Introduction The Discovery of Vortioxetine Clinical Development of Vortioxetine for the Treatment of MDD Uncovering Vortioxetine's Potential to Treat Cognitive Dysfunction in Patients with MDD Conclusion PART V. Antiulcer Drug Discovery DISCOVERY OF VONOPRAZAN FUMARATE (TAK-438) AS A NOVEL, POTENT AND LONG-LASTING POTASSIUM-COMPETITIVE ACID BLOCKER Introduction Limitations of PPIs and the Possibility of P-CABs Exploration of Seed Compounds Lead Generation from HTS Hit Compound 1 Analysis of SAR and Structure-Toxicity Relationship for Lead Optimization Selection of Vonoprazan Fumarate (TAK-438) as a Candidate Compound Preclinical Studiy of TAK-438 Clinical Study of TAK-438 Discussion Conclusion PART VI. Cross-Therapeutic Drug Discovery (Respiratory Diseases/Anti-Cancer) DISCOVERY AND DEVELOPMENT OF NINTEDANIB: A NOVEL ANTIANGIOGENIC AND ANTIFIBROTIC AGENT Introduction Structure-Activity Relationships of Oxindole Kinase Inhibitors and the Discovery of Nintedanib Structural Research Preclinical Pharmacodynamic Exploration Nonclinical Drug Metabolism and Pharmacokinetics Clinical Pharmacokinetics Toxicology Phase III Clinical Data Other Oncology Studies Conclusions Index.
  • (source: Nielsen Book Data)9783527800322 20170313
Retaining the successful approach found in the previous volume in this series, the inventors and primary developers of drugs that successfully made it to market tell the story of the drug's discovery and development and relate the often twisted route from the first candidate molecule to the final marketed drug. 11 selected case studies describe recently introduced drugs that have not been previously covered in textbooks or general references. These range across six different therapeutic fields and provide a representative cross-section of the current drug development efforts. Backed by copious data and chemical information, the insight and experience of the contributors makes this one of the most useful training manuals that a junior medicinal chemist can hope to find and has won the support and endorsement of IUPAC.
(source: Nielsen Book Data)9783527800346 20170313
1 online resource.
  • Taste receptor gene expression outside the gustatory system.- Medicinal Chemistry of Plant Naturals as Agonists/Antagonists for Taste Receptors.- Chemical activation of TRP channels in taste and smell.- Olfactory transduction channels and their modulation by varieties of volatile substances.- Chemosensory G protein-coupled receptors (GPCR) in blood leukocytes.- Neuronal functions and emerging pharmacology of TAAR1.
  • (source: Nielsen Book Data)9783319489254 20170502
Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.
(source: Nielsen Book Data)9783319489254 20170502
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