Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: C. Robin Ganellin,Roy Jefferis,Stanley M. Roberts
Publsiher: Academic Press
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780123977700

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Introduction to Biological and Small Molecule Drug Research and Development provides, for the first time, an introduction to the science behind successful pharmaceutical research and development programs. The book explains basic principles, then compares and contrasts approaches to both biopharmaceuticals (proteins) and small molecule drugs, presenting an overview of the business and management issues of these approaches. The latter part of the book provides carefully selected real-life case studies illustrating how the theory presented in the first part of the book is actually put into practice. Studies include Herceptin/T-DM1, erythropoietin (Epogen/Eprex/NeoRecormon), anti-HIV protease inhibitor Darunavir, and more. Introduction to Biological and Small Molecule Drug Research and Development is intended for late-stage undergraduates or postgraduates studying chemistry (at the biology interface), biochemistry, medicine, pharmacy, medicine, or allied subjects. The book is also useful in a wide variety of science degree courses, in post-graduate taught material (Masters and PhD), and as basic background reading for scientists in the pharmaceutical industry. For the first time, the fundamental scientific principles of biopharmaceuticals and small molecule chemotherapeutics are discussed side-by-side at a basic level Edited by three senior scientists with over 100 years of experience in drug research who have compiled the best scientific comparison of small molecule and biopharmaceuticals approaches to new drugs Illustrated with key examples of important drugs that exemplify the basic principles of pharmaceutical drug research and development

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: James Samanen
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061978

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Successful drugs have a good return on investment by bringing in considerably more revenue than the expenses of discovery, development, and manufacturing. Successful drugs pay for all drug projects, those that fail and those that have yet to fail or succeed. Most research and development (R&D) projects fail. Since R&D is the future of the company, a lot is at stake in the business of R&D. This chapter considers the organization of biopharmaceutical R&D, as well as various organizational experiments, that are already under way, that deal with the enormous risk and cost of biopharmaceutical R&D. There is a fairly uniform sequence of events involved in the discovery and development of biopharmaceuticals. The Stage-Gate Organization of the project pipeline is described along with stage-related goals. The high attrition in the industry is examined as well as reasons for project failure, particularly in the clinic. The fact that most projects fail in the biopharmaceutical industry means that risk, the probability that a project will fail, influences a number of key behaviours in biopharmaceutical R&D. The manner in which risk influences probability of success, cost, value and corporate commitment is considered. Not all discoveries occur within a company – many are in-licenced. Reduced revenues challenge a company's ability to develop all its assets, increasing the demands on project and portfolio management, and for out-licencing or partnering. In large biopharmaceutical companies, resource tends to be organized into business units, therapy areas, line departments, and platform technology groups. In the new era of reduced profits many companies are moving away from vertical integration towards decentralization, performing many to most functions in other companies, and in the extreme, towards virtual drug discovery and development. The risks and benefits with the external allocation of resource via outsourcing and partnering are discussed. Experiments with the organizational model of biopharmaceutical R&D are explored which aim to reduce risk, increase success and efficiency, including attempts to be big and small at the same time, planning for failure, and open innovation. There are also external revenue challenges, including generics competition and third-party payer constraints. On the upside are a number of opportunities to increase revenue, including new biologics and new areas of exploration – epigenetics and gene therapy – and by expanding markets into rapidly developing countries. Managers face complex challenges to the business of biopharmaceutical R&D. But, regardless of the type of company or set of partnered companies, academic institutions and service organizations that perform biopharmaceutical R&D, to a large extent the sequence of events in which a drug is discovered and developed will always be the same. And as long as the industry can continue to find new therapies that positively impact the lives of patients, it will continue to be an exciting and challenging industry.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: James Samanen
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061954

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Biotechnology has given rise to a broad range of biotherapies or biologics, including biomolecular drugs, vaccines, cell or gene therapies. This chapter focuses on biomolecular drugs, namely monoclonal antibodies (Mabs), cytokines, tissue growth factors and therapeutic proteins. Prior to the US approval of recombinant human insulin in 1982, biomolecular drugs were extracted from natural sources. The tools of molecular biology have dramatically increased the discovery and development of new biopharmaceuticals. The most obvious difference between small-molecule drugs (SMDs) and biomolecular drugs is size, like the difference in weight between a bicycle and a business jet. SMDs and biomolecular drugs are compared in this chapter by structure, molecular weight, preparation, physicochemical properties, and route of administration, as well as distribution, metabolism, serum half-life, dosing regimen, species reactivity, antigenicity & hypersensitivity, clearance mechanisms, drug–drug interactions, and pharmacology. This chapter reviews the differences and similarities in the various stages of drug discovery and development, with respect to cost, probability of success and cycle time. The clinical metrics of overall clinical success rate, stage-related success rate, and clinical cycle time are examined for SMDs and biomolecular drugs. The hybrid class of peptide drugs tends to be equated with biologics, due to their amino acid content and because oral activity is rare. But peptides truly bridge the gap between small molecules and biologics, in terms of physical properties, range of therapy areas and means of production. This chapter summarizes the similarities and differences of peptide drugs with SMDs and biomolecular drugs. The manner in which these agents compare as products with respect to manufacturing and pricing are considered. Two case studies are presented—the antagonists where small-molecule, peptide and Mab agents have competed in the market, and Her2 inhibitors where small-molecule and Mab agents may ultimately synergize as a combination product. Biomolecular drugs have levelled the playing field. All the “big Pharma” companies now have the capacity to develop both types of drugs. Conversely the larger biotech companies are developing the capacity for small-molecule synthesis. Now, with many blockbuster biologics nearing patent expiration, biosimilars are on the way. It's no longer a question of “choose which type”—one will need to know how to discover and develop either type of drug.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Michael Stocks
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061930

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Drug discovery of small molecules from target selection through to clinical evaluation is a very complex, challenging but rewarding area of drug discovery. There are many obstacles along the journey from initial hit-finding activities, through optimization of compounds and eventually to delivery of robust candidate drugs (CDs) for clinical evaluation. This chapter presents key issues and literature solutions with respect to the optimization of hits into CDs. Details of the key hit-finding activities namely high-throughput screening, virtual screening, natural products, fragment-based drug discovery and fast-follower approaches are discussed. Key aspects of compound quality such as lipophilicity, solubility, drug metabolism and pharmacokinetic, plasma protein binding and cytochrome P450 inhibition/induction are discussed as well as potential safety liabilities such as human ether-a-go-go related gene, genotoxicity and phospholipidosis, Finally successful hit-to-lead and lead optimization case studies are presented to illustrate and highlight the key principles.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Jill M. Carton,William R. Strohl
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061947

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Throughout human history, the morbidity and mortality associated with human disease has driven medical science into an ever-expanding quest for treatment and cure. Over the past century, a therapeutic approach complementing chemical drugs has been developing which uses proteins and peptides in the treatment of disease. Many innovative protein therapeutic platforms are currently being employed and continue to be developed to attain cures in areas of unmet medical need; these include direct copies of natural protein structure and function as well as proteins with completely novel functionality. Today, protein therapeutics represents the fastest growing sector in the pharmaceutical industry and comprises 16% of prescription drug sales in 2011.

Small Molecule Drug Discovery

Small Molecule Drug Discovery
Author: Andrea Trabocchi,Elena Lenci
Publsiher: Elsevier
Total Pages: 356
Release: 2019-11-23
Genre: Science
ISBN: 9780128183502

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Small Molecule Drug Discovery: Methods, Molecules and Applications presents the methods used to identify bioactive small molecules, synthetic strategies and techniques to produce novel chemical entities and small molecule libraries, chemoinformatics to characterize and enumerate chemical libraries, and screening methods, including biophysical techniques, virtual screening and phenotypic screening. The second part of the book gives an overview of privileged cyclic small molecules and major classes of natural product-derived small molecules, including carbohydrate-derived compounds, peptides and peptidomimetics, and alkaloid-inspired compounds. The last section comprises an exciting collection of selected case studies on drug discovery enabled by small molecules in the fields of cancer research, CNS diseases and infectious diseases. The discovery of novel molecular entities capable of specific interactions represents a significant challenge in early drug discovery. Small molecules are low molecular weight organic compounds that include natural products and metabolites, as well as drugs and other xenobiotics. When the biological target is well defined and understood, the rational design of small molecule ligands is possible. Alternatively, small molecule libraries are being used for unbiased assays for complex diseases where a target is unknown or multiple factors contribute to a disease pathology. Outlines modern concepts and synthetic strategies underlying the building of small molecules and their chemical libraries useful for drug discovery Provides modern biophysical methods to screening small molecule libraries, including high-throughput screening, small molecule microarrays, phenotypic screening and chemical genetics Presents the most advanced chemoinformatics tools to characterize the structural features of small molecule libraries in terms of chemical diversity and complexity, also including the application of virtual screening approaches Gives an overview of structural features and classification of natural product-derived small molecules, including carbohydrate derivatives, peptides and peptidomimetics, and alkaloid-inspired small molecules

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Wolfgang Jelkmann
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128062005

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The renal hormone erythropoietin (Epo) is essential for the viability and proliferation of the erythrocytic progenitors generating reticulocytes in the bone marrow. Human Epo consists of a chain of 165 amino acid residues and four glycans. The synthesis of Epo is strongly stimulated by hypoxia. Epo deficiency is the primary cause of the anaemia in chronic kidney disease (CKD). For anaemia treatment recombinant human Epo (rhEpo/epoetin and epoetin) is very useful. The drug substance is generally manufactured in EPO complementary DNA (cDNA) transfected Chinese hamster ovary cell cultures. rhEpo therapy is beneficial not only for CKD patients but also for anaemic cancer patients receiving chemotherapy. The expiry of the patents for the first original rhEpo formulations has initiated the production of similar biological medicinal products (‘biosimilars’). The term ‘biosimilar’ should only be used for a medicinal product approved on a strict regulatory pathway (i.e. European Medicines Agency, Food and Drug Administration, etc.). Unfortunately, many claimed ‘biosimilars’ have not been through an approval authority. Furthermore, rhEpo analogues with prolonged survival in circulation (‘biobetter’) have been developed and synthetic Epo mimetic peptides have been developed for therapy. The biological role of Epo outside the bone marrow is the focus of current research.

Basic Principles of Drug Discovery and Development

Basic Principles of Drug Discovery and Development
Author: Benjamin E. Blass
Publsiher: Academic Press
Total Pages: 712
Release: 2021-03-30
Genre: Medical
ISBN: 9780128172155

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Basic Principles of Drug Discovery and Development presents the multifaceted process of identifying a new drug in the modern era, which requires a multidisciplinary team approach with input from medicinal chemists, biologists, pharmacologists, drug metabolism experts, toxicologists, clinicians, and a host of experts from numerous additional fields. Enabling technologies such as high throughput screening, structure-based drug design, molecular modeling, pharmaceutical profiling, and translational medicine are critical to the successful development of marketable therapeutics. Given the wide range of disciplines and techniques that are required for cutting edge drug discovery and development, a scientist must master their own fields as well as have a fundamental understanding of their collaborator’s fields. This book bridges the knowledge gaps that invariably lead to communication issues in a new scientist’s early career, providing a fundamental understanding of the various techniques and disciplines required for the multifaceted endeavor of drug research and development. It provides students, new industrial scientists, and academics with a basic understanding of the drug discovery and development process. The fully updated text provides an excellent overview of the process and includes chapters on important drug targets by class, in vitro screening methods, medicinal chemistry strategies in drug design, principles of in vivo pharmacokinetics and pharmacodynamics, animal models of disease states, clinical trial basics, and selected business aspects of the drug discovery process. Provides a clear explanation of how the pharmaceutical industry works, as well as the complete drug discovery and development process, from obtaining a lead, to testing the bioactivity, to producing the drug, and protecting the intellectual property Includes a new chapter on the discovery and development of biologics (antibodies proteins, antibody/receptor complexes, antibody drug conjugates), a growing and important area of the pharmaceutical industry landscape Features a new section on formulations, including a discussion of IV formulations suitable for human clinical trials, as well as the application of nanotechnology and the use of transdermal patch technology for drug delivery Updated chapter with new case studies includes additional modern examples of drug discovery through high through-put screening, fragment-based drug design, and computational chemistry

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Jennifer Ann Littlechild
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061923

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This chapter covers the general features of protein structure and recent advances in structural bioinformatics. The importance of the three-dimensional structure of the protein target in order to understand its mechanism of action as an aid for drug design is illustrated by specific examples of enzyme inhibition, receptor interactions and drugs binding to structural proteins. The impact of proteomics and bioinformatics is stressed, while protein interactions with other proteins and different biological macromolecules are discussed.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Denis Mulleman,Marc Ohresser,Hervé Watier
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128062043

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Parallel studies in septic shock and cancer led to the discovery of the endogenous factors named cachectin and tumour necrosis factor (TNF), respectively, that were shown to be structurally and functionally similar. Further studies identified two forms of TNF, TNF-α and TNF-β. The anticipation that specific anti-TNF antibody might have therapeutic potential in the resolution of sepsis was not realized; however, anti-TNF-α agents have been shown to have dramatic therapeutic efficacy in a number of inflammatory diseases. Currently, there are five anti-TNF agents approved that are equally effective in the treatment of rheumatoid arthritis but exhibit differing efficacy in other inflammatory conditions. Three are full-length immunoglobulin G (IgG) anti-TNF-α antibodies, one is an anti-TNF-α Fab fragment and another, a TNF receptor–Fc fusion protein. Their different structures reflect recent advances in our ability to apply genetic engineering for patient benefit.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Charles W. Richard
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128062012

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Lysosomal storage disorders (LSDs) represent a group of about 50 genetic disorders caused by deficiencies of lysosomal proteins. The missing lysosomal protein causes a build-up of toxic metabolites in the cells of patients, leading to progressive multisystem disease and premature death. Although individually rare, the combined prevalence of all lysosomal disorders is estimated to be 1 in 8000 births. This chapter describes progress in several different LSD treatment modalities including enzyme replacement therapy, haematopoietic stem cell therapy, chaperone (enzyme stabilization) therapy, and substrate reductions therapy, and highlights new treatment directions for the future.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: null Hasmann
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061992

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HER2 (ErbB-2) is a member of the human epidermal growth factor receptor tyrosine kinase family which is involved in the regulation of cell proliferation, survival and differentiation. Soon after its discovery, HER2 was shown frequently to be overexpressed in breast cancer and was associated with a worse prognosis. It was identified as a target for drug development and molecular cloning of the gene and expression in cell lines provided a vehicle for the selection of HER2-specific antibodies. The monoclonal antibody trastuzumab is the first HER2-targeting drug approved for cancer treatment. By significantly extending the time to disease progression and overall survival of patients, it has become established in all treatment lines of early and metastatic HER2-positive breast cancer, as well as in HER2-positive advanced metastatic gastric or gastroesophageal junction cancer. Combination of trastuzumab with pertuzumab, a second antibody binding to a distinct epitope on HER2 which implies a different mode of action, took the treatment of HER2-positive metastatic breast cancer to the next level of success. Finally, trastuzumab emtansine is an antibodydrug conjugate that retains all pharmacodynamic activities of trastuzumab and delivers a toxic maytansinoid directly to the tumour cells. Current clinical results indicate that trastuzumab emtansine may be more efficacious and less toxic than trastuzumab plus chemotherapy, and further improvement is expected in combination with pertuzumab.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Arun K. Ghosh,Bruno D. Chapsal
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128062036

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The development of HIV protease inhibitors (PIs) and their inclusion in highly active antiretroviral therapies (HAARTs) marked the beginning of a treatment breakthrough in the management of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The HAART treatment regimen can cut HIV viral load to undetectable levels. Nonetheless, the rapid emergence of HIV drug resistance has continued to seriously compromise long-term treatment options for HIV-infected patients. Our structure-based design strategy to develop PIs that specifically target the enzyme's backbone atoms has resulted in a number of very potent inhibitors with superior drug resistance profiles. Of particular note, our development of stereochemically defined bis(tetrahydrofuranyl) urethane as a high-affinity P2 ligand has led to the development of exceedingly potent inhibitors. One of these inhibitors, darunavir, has shown exceptional potency against the HIV-1 virus and superior activity against multi-PI-resistant viral strains. Our backbone binding strategy was corroborated with detailed crystal structure analyses of darunavir-bound protease complexes which revealed a series of conserved interactions between the inhibitor and key backbone atoms of HIV-1 protease. Darunavir first received accelerated US Food and Drug Administration approval in 2006 for highly treatment-experienced patients with little therapeutic options. It has now become a leading PI in the fight against HIV infection and drug resistance.

Introduction to Biological and Small Molecule Drug Research and Development

Introduction to Biological and Small Molecule Drug Research and Development
Author: Matthew P. Coghlan,David Fairman
Publsiher: Elsevier Inc. Chapters
Total Pages: 472
Release: 2013-05-07
Genre: Science
ISBN: 9780128061961

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The increasing global prevalence of type 2 diabetes represents a significant burden of disease for afflicted patients and for health care systems. In the developed world poorly controlled diabetes is the leading cause of non-traumatic amputation, blindness and end-stage renal disease requiring dialysis and kidney transplant. Additionally, diabetes represents a significant risk factor for the development of cardiovascular disease with its associated morbidity and premature death. Currently available glucose lowering drugs used to treat type 2 diabetes do not impede progression of the disease. Therefore, as the disease progresses these agents rapidly lose efficacy, first as monotherapy and then in combination, resulting in poorly controlled disease. Clearly, there is a significant need for novel glucose lowering drugs for type 2 diabetes that will deliver sustained efficacy over several years by impeding disease progression. Such agents would reduce the risk of developing the microvascular complications of diabetes that ultimately result in amputation, blindness and kidney transplant. Novel glucose lowering drugs should ideally also exhibit a positive impact on the increased cardiovascular risk associated with diabetes. The incretin-based therapies first entered the market in the mid 2000’s and were heralded for their potential to impede progression of type 2 diabetes and to reduce cardiovascular risk. Through mimicking the actions of the gut incretin hormone GLP-1, these drugs had been shown to lower blood glucose in clinical trials by potentiating glucose stimulated insulin secretion from pancreatic β-cells. Moreover, data from preclinical rodent disease models and isolated human pancreatic islets suggested that these novel agents could preserve pancreatic β-cell function and thus impede disease progression. Further preclinical and clinical data supported the notion that these drugs could also aid blood glucose control by suppressing glucagon secretion, slowing gastric emptying and by suppressing appetite. The incretin-based drugs have potential to reduce cardiovascular risk through their ability to reduce body weight, blood pressure and atherogenic blood lipids. This chapter will review the incretin-based therapies and consider what impact these new drugs have made to date in the pharmacotherapy of type 2 diabetes. The incretin-based therapies are of particular relevance to this book as this class of drugs is composed of two sub-classes, injectable peptide drugs and oral small molecule drugs. The similarities and differences between these small molecule and peptide drugs are described.

Epi Informatics

Epi Informatics
Author: Jose Medina-Franco
Publsiher: Academic Press
Total Pages: 440
Release: 2016-02-24
Genre: Medical
ISBN: 9780128028094

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Epi-Informatics: Discovery and Development of Small Molecule Epigenetic Drugs and Probes features multidisciplinary strategies with strong computational approaches that have led to the successful discovery and/or optimization of compounds that act as modulators of epigenetic targets. This book is intended for all those using or wanting to learn more about computational methodologies in epigenetic drug discovery, including molecular modelers, informaticians, pharmaceutical scientists, and medicinal chemists. With a better understanding of different molecular modeling and cheminformatic approaches, readers can incorporate these techniques into their own drug discovery projects that may involve chemical synthesis and medium- or high-throughput screening. In addition, this book highlights the significance of epigenetic targets to the public health for molecular modelers and chemoinformatians. The goal of this reference is to stimulate ongoing multidisciplinary research and to further improve current computational methodologies and workflows in order to accelerate the discovery and development of epi-drugs and epi-probes. Focuses on the discovery of epi-drugs as candidates to be used in therapy including combined therapies Describes new computational methodologies and screening assays utilizing recent and emerging novel structural data Highlights the discovery, development and optimization of epi-probes, which are molecular probes that elucidate epigenetic mechanisms Includes important topics such as computational-guided optimization of epi-hits, virtual screening to identify novel compounds for epigenetic targets, development and mining of epigenetic molecular databases, SAR modeling of screening data and much more