Benzodiazepine Based Drug Discovery

Benzodiazepine-Based Drug Discovery covers benzodiazepines and benzothiazepines, which constitute two pivotal classes of heterocyclic compounds widely used as core structures of medicinal drugs for the treatment of depression, epilepsy, seizures and muscle spasms. 1,4-Benzodiazepine, 1,5-benzodiazepine, and 1,5-benzothiazepine are the most studied groups of benzodiazepines and benzothiazepines because of their outstanding potential biological activities. This book offers a broad range of recent developments and detailed coverage of the synthesis and biological activities of the drugs based on benzodiazepine and benzothiazepine matrixes, and is an ideal reference guide to researchers working in organic and medicinal chemistry. The importance of these privileged pharmacophores is not limited to the treatment of psychotic disorders because minor changes in the structures can generate various biological activities. They represent a wide range of therapeutic functions such as anticonvulsant, antianxiety, anti-depressant, antiviral, anti-HIV, anti-inflammatory, anticoagulant, anti-obesity, endothelin antagonist, cholecystokinin antagonist, and vasopressin receptor antagonist activities. Presents detailed coverage of chemical structures and practical synthetic methods of benzodiazepines and benzothiazepines in drug discovery Compiles detailed in vivo and in vitro biological activity data of 1,4-benzodiazepine- and 1,5-benzodiazepine-based drugs that will help researchers design and develop innovative drugs Discusses promising avenues and potential challenges in the development of new benzodiazepines and benzothiazepines in medicinal drug synthesis

One strategy to expedite the discovery of new drugs, a process that is somewhat slow and serendipitous, is the identification and use of privileged scaffolds. This book covers the history of the discovery and use of privileged scaffolds and addresses the various classes of these important molecular fragments. The first of the benzodiazepines, a class of drugs that is powerful for treating anxiety, may not have been discovered had it not been for a chance experiment on the contents of a discarded flask found during a lab clean-up. Some years later, scientists discovered that benzodiazepine derivatives were also effective in treating other diseases. This class of molecules was the first to be described as privileged in the sense that it is especially effective at altering the course of disease. Other privileged molecular structures have since been discovered, and since these compounds are so effective at interacting with numerous classes of proteins, they may be an effective starting point to look for new drugs against the supposedly “undruggable” proteins. Following introductory chapters presenting an overview, a historical perspective and the theoretical background and findings, main chapters describe the structure of privileged structures in turn and discuss major drug classes associated with them and their syntheses. This book provides comprehensive coverage of the subject through chapters contributed by expert authors from both academia and industry and will be an excellent reference source for medicinal chemists of a range of disciplines and experiences.

A comprehensive guide to privileged structures and their application in the discovery of new drugs The use of privileged structures is a viable strategy in the discovery of new medicines at the lead optimization stages of the drug discovery process. Privileged Structures in Drug Discovery offers a comprehensive text that reviews privileged structures from the point of view of medicinal chemistry and contains the synthetic routes to these structures. In this text, the author—a noted expert in the field—includes an historical perspective on the topic, presents a practical compendium to privileged structures, and offers an informed perspective on the future direction for the field. The book describes the up-to-date and state-of-the-art methods of organic synthesis that describe the use of privileged structures that are of most interest. Chapters included information on benzodiazepines, 1,4-dihydropyridines, biaryls, 4-(hetero)arylpiperidines, spiropiperidines, 2-aminopyrimidines, 2-aminothiazoles, 2-(hetero)arylindoles, tetrahydroisoquinolines, 2,2-dimethylbenzopyrans, hydroxamates, and bicyclic pyridines containing ring-junction nitrogen as privileged scaffolds in medicinal chemistry. Numerous, illustrative case studies document the current use of the privileged structures in the discovery of drugs. This important volume: Describes the drug compounds that have successfully made it to the marketplace and the chemistry associated with them Offers the experience from an author who has worked in many therapeutic areas of medicinal chemistry Details many of the recent developments in organic chemistry that prepare target molecules Includes a wealth of medicinal chemistry case studies that clearly illustrate the use of privileged structures Designed for use by industrial medicinal chemists and process chemists, academic organic and medicinal chemists, as well as chemistry students and faculty, Privileged Structures in Drug Discovery offers a current guide to organic synthesis methods to access the privileged structures of interest, and contains medicinal chemistry case studies that document their application.

The development of Valium by Roche Pharmaceutical and the entire benzodiazepine group of active substances was among the greatest accomplishments in 20th-century pharmacology. Good Chemistry combines a detailed account of this momentous development with an engaging biography of Leo Sternbach, the brilliant chemist who invented Valium and whose achievements heralded the beginning of a new era in research and therapeutics. This thought-provoking biographical history: Tells the fascinating life story of one of the 20th century's premier chemists Traces the developments that led to the invention of Valium Provides a cultural history of Valium and its impact on society

The story of the benzodiazepines is a fascinating one: the synthesis of a long series of inert compounds and the abandonment of the project: months later, the renewal of the project and the discovery that this compound R05-0690 (Librium ®) was a sedative and muscle relaxant in laboratory animals: the recognition that its postulated structure was wrong and that it was in fact a member of an entirely new chemical class: the excitement caused by the discovery of the powerful taming effect of the drug in wild animals: the even greater excitement in medical circles when its dramatic anxiety relieving effects were cstablished in humans: the subsequent enormous world wide usc of drugs of the benzodiazepine group. I have reason to know the story well for during that period I worked in various capacities in research, marketing and manage ment in the British subsidiary of F. Hoffmann-Ia Roche. It was during this period that I became interested in whether dependence on benzodiazepines could occur and if so to what extent, but felt that this could be examined best from outside the concern. Having now retired from Roche back to academic medicine I have taken the opportunity to examine and analyse the evidence.

Can drug development and evaluation be improved by the use of positron emission tomography (PET)? PET is now well established and many PET centres participate in networks that warrant the quality of their research. PET allows one to follow the effect of a drug on a variety of patients' metabolic parameters. In addition, PET may be used to follow the fate in vivo of a compound, allowing visualisation of its binding to specific receptors and a direct study of the mechanism of drug action in normal and pathological situations. The book shows the fields in which PET offers new and unique information for the development of drugs (conception, toxicity, pharmacokinetics and metabolism, clinical research, and relations between clinical and biological effects) and evaluates fields in which PET may shorten the development time of drugs. Audience: Professionals in the pharmaceutical industry in all areas of drug discovery and pharmacology, pre-clinical testing, pharmacokinetics and metabolism, clinical evaluation, registration and regulatory affairs. Government health authority representatives who assess data and documentation on new drug development and radiopharmaceuticals. Academic experts concerned with any of these areas.

Understanding and addressing the current opioid crisis requires knowledge of endogenous opioids (endorphins and enkephalins), but there is now evidence for a benzodiazepine crisis. Are there endogenous benzodiazepine-like substances—and what do they do? How do they affect antianxiety drugs and their adverse effects? Do they explain enigmatic prolonged benzodiazepine withdrawal syndrome? This book raises important questions about the clinical consequences of ignoring the existence of or understanding the potential influence of endogenous benzodiazepines on the therapeutic effect of benzodiazepines, their adverse effects, and the problems of withdrawal from them and other benzodiazepine receptor agonists. FEATURES Discusses endogenous benzodiazepine-like substances—what do they do, and do they affect antianxiety drugs and their adverse effects? Presents information on enigmatic prolonged benzodiazepine withdrawal syndrome Describes the compounds acting at the BDZ binding sites, both exogenous (classical BDZ drugs and BDZ from food and plants) and endogenous (endozepines) Assesses the putative interactions in physiology, pathology, and pharmacology of the compounds acting at the BDZ binding sites Dr. Raffa is Adjunct Professor at the University of Arizona College of Pharmacy and Professor Emeritus at Temple University School of Pharmacy. He has co-authored or edited several books on pharmacology and thermodynamics, is a co-editor of two journals, is a past president of the Mid-Atlantic Pharmacology Society, and is the recipient of research and teaching awards. Dr. Amantea is Associate Professor of Pharmacology at the Department of Pharmacy, Health and Nutritional Sciences of the University of Calabria (Italy), where she is the leader of the Stroke Research Unit at the Section of Preclinical and Translational Pharmacology operating in the frame of the Italian Stroke Organization (ISO) Basic Science. She is a member of the Editorial Board and the Guest Editor of the 2016 Neuroscience section of Current Opinion in Pharmacology (Elsevier), and the founder and the editor of the CRC Press Frontiers in Neurotherapeutics series.