Medicinal Chemistry

Description

This textbook is an overview of the subject of medicinal chemistry within the context of drug design and discovery. Both of us were trained as synthetic organic chemists and had our “first” careers in medicinal chemistry departments at major pharmaceutical companies. Upon moving into academia, we both took on teaching a one-semester class in medicinal chemistry. Anyone who has taught this type of course quickly realizes the difficulty in bringing together the many aspects that comprise this subject, such as organic chemistry, pharmacology, and biochemistry, as well as introducing therapeutic areas in medicinal chemistry in just one semester. After teaching this course for many years using various review articles as text, as well as material written ourselves, we decided to write this textbook. We have tried to write a text that includes the historical background of drug discovery but emphasizes modern practices in design, discovery, and development. We focus on drug targets and how current knowledge of these targets drives medicinal chemistry and drug discovery. While it is not possible to cover all therapeutic areas in a one-semester text, selected areas and classes of drugs are also included. Overall, we intend for this text to meet the need for a modern, onesemester textbook that ties together the many different aspects of medicinal chemistry as it is currently practiced. The target audience is primarily upper-level undergraduate students and beginning graduate students in organic chemistry and medicinal chemistry. Other students who might find the text useful include pharmacy students and anyone planning to pursue a career in the drug discovery field. In addition to science majors, we have had students from fields as diverse as finance, engineering, and biomedical ethics take our courses, all with a common interest in learning about drug discovery. The book should also be useful for professional scientists, such as chemists, biologists, and patent professionals, who are just entering the drug discovery field and may not have had direct experience with medicinal chemistry. It is expected that those using this textbook have a basic knowledge of organic chemistry as well as basic biology. To present this broad subject in a way that is logical and covers essential topics in a one-semester format, our approach is to divide the text into three sections. PART I, Drug Discovery and Development: the first five chapters cover historical background in drug discovery, as well as the modern drug discovery and development process, with an emphasis on medicinal chemistry strategies used in various phases. These chapters give the essential background of hit and lead discovery, modifications driven by knowledge of both target and pharmacophore structure, common medicinal chemistry strategies, and the central importance of pharmacokinetics. They provide the background that subsequent chapters build upon. PART II, Classes of Drug Targets: Chapters 6-9 focus on the major drug targets, namely, their structure and function and how medicinal chemists approach each. Examples of specific drugs developed for each type of target are included. Targets include receptors and ion channels, enzymes, protein-protein and lipid interactions, and nucleic acids. Each of those is broken down into more specific classes of important drug targets. These chapters can be covered in any order but reference topics in Chapters 1-5. PART III, Selected Therapeutic Areas: the final chapters, 10-13, are devoted to selected important therapeutic areas. While there are many more chapters that could have been written on additional areas of interest, these topics were selected as examples that tie together components introduced in the earlier chapters and represent both historically important agents and future opportunities. Those topics included are anti-cancer, antibacterial, and antiviral drugs and drugs acting on the central nervous system. A subset of Chapter 13 is devoted to drugs of abuse, informed by student interest on this topic. Any of these last chapters on specific therapeutic areas can be considered optional or used independently, but they also rely on the material covered in Chapters 1-9. CONTENTS PART I DRUG DISCOVERY AND DEVELOPMENT Chapter 1 Historical perspective and overview of drug discovery Historical Perspective of the Practice of Medicinal Chemistry 1.1 Many medicines were originally isolated from plants 1.2 Semisynthetic drugs are prepared from natural products Overview of the Practice of Medicinal Chemistry in the Modern Era 1.3 Identification of complex structures began in the early 1900s 1.4 Advances in total synthesis allow access to natural products and analogs 1.5 Medicinal chemistry currently is based on the molecular causes of disease Summary Case Study 1 Discovery of Artemisinin Case Study 2 Discovery Of Ingenol Mebutate Review Questions Application Questions Further Reading Chapter 2 Drug discovery: hit and lead identification Overview of Drug Discovery Process Identification of Hits and Leads 2.1 Various types of assays are used in screening for hit and lead identification Sources of Hits and Leads in Drug Discovery: Compounds with Known Bioactivity 2.2 Plant-based sources are the starting points for many drugs 2.3 Microbes and higher animals may be sources for hits, leads, and drugs 2.4 Hits and leads are often based on natural ligands 2.5 Compounds with reported bioactivity are important sources of hits and leads 2.6 Clinical observations may uncover unexpected activities of known bioactive compounds Sources of Hits and Leads in Drug Discovery: Synthetic Libraries 2.7 Legacy libraries contain compounds from prior discovery campaigns 2.8 Combinatorial libraries are sets of closely related analogs that can be prepared by parallel or split-pool synthesis 2.9 Diversity-oriented synthesis is another strategy used in designing synthetic libraries Methods for Screening Compound Libraries 2.10 High-throughput screening assays large numbers of compounds by a variety of different techniques 2.11 Fragment-based screening detects direct binding to a protein target 2.12 Virtual libraries can be screened by computational algorithms Identification of High-Quality Hits from Screening 2.13 False positives and nuisance compounds need to be eliminated from primary hit lists 2.14 Hits identified in screening campaigns need to be prioritized Summary Case Study 1 Example of Fragment-Based Screening Case Study 2 Example of Virtual Screening Review Questions Application Questions Further Reading Chapter 3 Lead optimization: drug-target interactions and the pharmacophoreOptimization of Drug-Target Interactions 3.1 Optimization of binding depends on specific molecular interactions 3.2 Specific interactions contribute to the overall binding of drugs to their targets Tools Used to Develop Structure-Activity Relationships 3.3 Historical methods for quantifying structure-activity relationships were based on physicochemical parameters 3.4 Ligandand structure-based drug design are modern strategies that rely on knowledge of the pharmacophore 3.5 Pharmacophore models are widely used in ligand-based drug design 3.6 Structure-based drug design is based on the structure of the drug target Summary Case Study 1 Example of The Use of A Pharmacophore Model in Virtual Screening Case Study 2 Example of the Use of Structure-Based Drug Design Review Questions Application Questions Further Reading Chapter 4 Lead optimization: properties optimized and medicinal chemistry strategies Properties Evaluated During Lead Optimization 4.1 Biological activity is optimized as a component of the lead optimization process 4.2 Physical and pharmaceutical properties are optimized in parallel with biological properties Optimization of Lead Properties 4.3 Rules and metrics have been developed to aid the lead optimization process 4.4 Lipophilicity is optimized so that a drug can reach its target 4.5 Leads need to be optimized for solubility in aqueous media 4.6 Optimization of metabolic stability is a necessary component of lead optimization 4.7 Targeting strategies and the use of prodrugs improve drug properties Medicinal Chemistry Strategies Applied During Lead Optimization 4.8 Increasing steric bulk affects binding, lipophilicity, and metabolic stability 4.9 Bioisosteres are used as substitutions for specific functional groups 4.10 Scaffold hopping is a subset of bioisosterism 4.11 Incorporation of fluorine may affect potency and pharmaceutical properties 4.12 Transition-state mimetics are common features of enzyme inhibitors 4.13 Conformational constraints can be used to improve binding to the drug target 4.14 Privileged structures are structural templates found in multiple drugs Summary Case Study 1 Lead Optimization of Losartan Case Study 2 Discovery and Strategies Used in Development of Cimetidine to Treat Gastric Ulcers Review Questions Further Reading Chapter 5 The process of developing a drug from an optimized lead Patenting and Drug Discovery and Development 5.1 Three versions of patents are commonly filed during the drug discovery process Process Chemistry Research Characterization of Pharmacokinetic Properties of Leads 5.2 Absorption is one determinant of how much drug reaches its biological target 5.3 Distribution determines which tissues accumulate drugs 5.4 Metabolism and elimination are the body’s method for removing drugs Drug Toxicity Determination 5.5 Indications of toxicity are identified early in the drug discovery stage by in vitro assays 5.6 Toxicity testing is done with in vivo assays in multiple animal species5.7 Formulation of the final drug product Clinical Trials in Humans Summary Case Study 1 Discovery of Fluoxetine Case Study 2 Development of Rivaroxaban (Xarelto) Review Questions Application Questions Further Reading PART II CLASSES OF DRUG TARGETS Chapter 6 Receptors, ion channels, and transporters as drug targets G Protein-Coupled Receptors as Drug Targets 6.1 GPCRs are defined by structural features 6.2 Ligands bind to GPCRs and may activate or inactivate a receptor 6.3 Drug activity is classified by examining biological response as compared to dose 6.4 Theories have been developed to explain how drugs binding at the same receptor site may have different types of activity 6.5 Drugs acting at GPCRs include drugs to treat allergy, cardiovascular disease, asthma, and ulcers Ion Channels (Ionotropic Receptors) As Drug Targets 6.6 Ligand-gated ion channels open or close in response to binding of a drug or natural ligand 6.7 Neuromuscular blockers, sedatives, and anti-nausea agents are examples of drugs acting at LGICs 6.8 Voltage-gated ion channels open or close in response to changes in membrane potential 6.9 Blockers of sodium, calcium and potassium VGICs include local anesthetics, anticonvulsants, and anti-arrhythmia drugs Nuclear Receptors As Drug Targets 6.10 Drugs that target nuclear receptors are used to treat cancer, inflammation, and diabetes and to regulate the physiological effects of sex hormones Transporters As Drug Targets 6.11 Drugs acting at transporters treat a wide array of neuropsychiatric disorders, hypertension, and diabetes Summary Case Study 1 Discovery of Ramelteon Case Study 2 Discovery of Rosiglitazone Review Questions Application Questions Further Reading General G protein-coupled receptors Ion channels Nuclear receptors Transporters Ramelteon Rosiglitazone Web sites Chapter 7 Enzymes as drug targets Effect of Small-Molecule Modulators on Enzymes 7.1 Modulators are classified by how they interact with an enzyme 7.2 Effects on enzyme kinetics are used to characterize the mechanism of small-molecule modulators7.3 Enzymes are frequent targets of drug action Kinases and Kinase Inhibitor Drugs 7.4 Kinase inhibitors work through multiple binding modes and are effective anti-cancer drugs and anti-inflammatory agents Proteases and Protease Inhibitors 7.5 Protease inhibitors are designed on the basis of the enzyme’s mechanism of action and are useful for treating HIV and bacterial infections as well as cardiovascular disease Polymerases and Polymerase Inhibitors 7.6 Inhibitors of polymerases can mimic the substrate or bind at an allosteric site Esterases, Phosphodiesterases, and Their Inhibitors 7.7 Inhibitors of phosphodiesterases treat cardiovascular disease, respiratory disease, and erectile dysfunction Oxidoreductases, Cyclooxygenases, and Inhibitors 7.8 Inhibitors of HMG-CoA reductase are used to lower cholesterol levels 7.9 Inhibitors of cyclooxygenase are effective anti-inflammatory drugs Summary Case Study 1 Discovery of the Proteint Tyrosine Kinase Inhibitor Imatinib Case Study 2 Development of Enalapril Review Questions Application Questions Further Reading Chapter 8 Protein-protein and lipid structure interactions as drug targets Protein-Protein Interactions As Drug Targets 8.1 One strategy to prevent binding between two proteins is to mimic one of the protein partners 8.2 Modulators of protein-protein interactions may change the equilibrium of a multiprotein complex, and examples of such are valuable anti-cancer agents 8.3 Modulators of protein-protein interactions can reduce levels of misactive proteins, and examples are useful to treat rare diseases Lipids of Cell Membranes as Drug Targets 8.4 Drugs acting at lipids in membranes act as anti-infective agents Summary Case Study 1 Discovery of Taxol Case Study 2 Discovery of Maraviroc Review Questions Application Questions Further Reading Protein-protein interactions Tubulin modulators RGD mimetics Transthyretin Taxol Maraviroc Chapter 9 DNA and RNA as drug targets DNA as a Drug Target 9.1 Intercalation is one of the main mechanisms by which small molecules interact with DNA 9.2 Drugs may bind in the minor groove of DNA through reversible noncovalent interactions 9.3 Drugs that interact with DNA by irreversible mechanisms are anti-cancer agents 9.4 Compounds that cleave DNA after binding and generating free radicals are powerful drugs used to treat cancer RNA as a Drug Target9.5 Compounds targeting bacterial ribosomal RNA inhibit protein synthesis and are useful antiinfective agents 9.6 Antisense therapies targeting RNA are effective in treating rare diseases and infections Summary Case Study 1 Doxorubicin And Analogs Case Study 2 Discovery of Mipomersen Review Questions Application Questions Further Reading DNA drugs RNA drugs Actinomycins Mipomersen PART III SELECTED THERAPEUTIC AREAS Chapter 10 Anti-cancer drugs Drugs Targeting DNA Replication and Mitosis 10.1 Drugs may target DNA and DNA processing enzymes such as polymerase and topoisomerase 10.2 Drugs may target biosynthesis of DNA building blocks 10.3 Drugs may target structural proteins involved in cell division 10.4 Effects of antitumor compounds may be optimized by targeting delivery systems Drugs Targeting Oncogenes and Signaling Pathways 10.5 Kinase inhibitors target mutant or overexpressed kinases found in cancer cells Inhibition of Angiogenesis Drugs Targeting the Ubiquitin-Proteasome Pathway Drugs Targeting Epigenetic Processes 10.6 Nucleosides with modified bases can act as DNA methyltransferase inhibitors 10.7 Histone deacetylase inhibitors bind to zinc in the enzyme’s active site Drugs Targeting Hormone-Dependent Tumors Summary Case Study 1 Discovery of Vorinostat Case Study 2 Vismodegib: Inhibitor of Hedgehog Signaling Pathway Review Questions Application Questions Further Reading Chapter 11 Antiviral and antifungal agents Antiviral Agents: Common Viral Structures, Replication Process, and Impact Antiviral Drug Discovery Antiviral Drugs Targeting Viral Life Cycle 11.1 Drugs may target viral attachment or entry 11.2 Drugs may target uncoating of viral particles 11.3 Many antiviral drugs inhibit transcription by targeting the active site of polymerases 11.4 Prodrugs improve the properties and effectiveness of nucleosides 11.5 Some HIV drugs that target reverse transcriptase bind at allosteric sites 11.6 Viral protease inhibitors have been developed by use of structure-based drug design 11.7 Inhibitors of the hepatitis C virus NS5A replication complex exhibit antiviral activity 11.8 Drugs to treat retroviruses may target the viral integrase 11.9 Influenza drugs target viral budding Antifungal Agents: Common Fungal Structures, Replication Process, and Impact Antifungal Drug Discovery Drugs Targeting Fungi11.10 Polyene drugs target the fungal cell membrane 11.11 Azoles and allylamines inhibit ergosterol biosynthesis 11.12 Some antifungal drugs inhibit cell replication 11.13 Echinocandins inhibit fungal cell-wall synthesis Summary Case Study 1 Discovery of Daclatasvir Case Study 2 Discovery of Rilpivirine Review Questions Application Questions Further Reading HIV/HCV Acyclic nucleosides and phosphonates Neuraminidase inhibitors Antifungal agents Chapter 12 Antibacterial and antiparasitic drugs Antibacterial Agents: Bacterial Structure, Points of Drug Interaction, And Impact Antibacterial Drug Discovery Bacterial Cell-Wall Synthesis Inhibitors 12.1 -Lactam antibacterial compounds are the largest class of cell-wall synthesis inhibitors 12.2 Glycopeptide antibacterial agents inhibit cell-wall synthesis by a different mechanism than βlactams Bacterial Protein Synthesis Inhibitors 12.3 Aminoglycosides, tetracyclines, and erythromycins are protein synthesis inhibitors based on natural products 12.4 Oxazolidinones are inhibitors of protein synthesis Drugs Targeting Bacterial DNA Replication 12.5 Quinolone antibacterial agents inhibit DNA gyrase 12.6 Sulfonamide antibacterial compounds inhibit folic acid biosynthesis Drugs Affecting Bacterial Cell-Membrane Permeability Antiparasitic Drugs: Common Parasite Features, Infectious Process, and Impact Antiparasitic Drug Discovery 12.7 Current drugs used to treat malaria are derivatives of natural products 12.8 There are few effective treatments for trypanosomal diseases 12.9 Drugs that treat helminthic diseases are used in both veterinary and human medicine Summary Case Study 1 Discovery Of Linezolid Case Study 2 Sq109 For Multi-Drug-Resistant Tuberculosis Review Questions Application Questions Further Reading Chapter 13 Drugs acting on the central nervous system Drugs Targeting Anxiety and Depression 13.1 Positive allosteric modulators at the GABAA receptor are sedatives and anticonvulsants 13.2 Drugs that increase monoamine neurotransmitter levels or act as partial agonists at neurotransmitter receptors are antidepressants Drugs Targeting Psychosis 13.3 Typical antipsychotics act as dopamine receptor antagonists 13.4 The mechanism of atypical antipsychotics involves dopamine receptor antagonism combined with serotonin receptor antagonism 13.5 Drugs targeting glutamate and phosphodiesterase 10A have potential as antipsychotics Drugs Targeting Pain13.6 Drugs used to treat pain include opiates and nonsteroidal antiinflammatory drugs as well as antidepressants 13.7 Novel approaches to pain treatment include selective ion channel blockers 13.8 Selective serotonin agonists are used to treat migraine Drugs Targeting Neurodegeneration 13.9 Approved drugs to treat Alzheimer’s disease affect acetylcholine or glutamate levels 13.10 Recent approaches to modifying the course of Alzheimer’s disease have focused on decreasing production of amyloid plaques 13.11 Drugs developed to treat Parkinson’s disease are based on increasing dopamine levels Drugs of Abuse 13.12 Stimulants include both legal and illegal drugs 13.13 Hallucinogens include serotonin receptor agonists and N-methyl-d-aspartate antagonists 13.14 Cannabinoids have potential medical uses Summary Case Study 1 Development of Vilazodone Case Study 2 Discovery of Donepezil Review Questions Application Questions Further Reading Answers to End of Chapter Review Questions Glossary Index