精要速览系列——一先锋版 Instant notes Medicinal chemistry 医药化学 (影印版) G. Patrick FUDAN B030909096106B复旦图书馆 复旦大学图书馆 藏书之章 斜导桌 北京
CONTENTS Abbreviations Preface about the author Section A-The science of medicinal chemistry Al Introduction A2 From concept to market Section B- Drug targets B2 Receptors B3 Carrier proteins B4 Structural proteins B5 Nucleic acids 7734295 Section C- Pharmacokinetics Cl Pharmacokinetics C2 Drug absorption Drug distribution 425 C4 Drug metabolism 5 Drug excretion C6 Drug administration 15 8 Section D- Biological testing and bioassays DI Testing drugs esting drugs D3 Testing d Section E- Drug discovery El The lead compound E2 Natural sources of lead compounds E3 Synthetic sources of lead compounds ection F- Synthesis 112m5万7858 Fl. Synthetic considerations F2 Stereochemistry SectionG- Structure-activity relationships G1 Definition of structure-activity relationships G2 Binding interactions G3 Functional groups as binding groups m2巧 G5 Quantitative structure-activity relationships
v Section H- Target orientated drug design H1 Aims of drug design 141 H2 Computer aided drug design H3 Simplification of comple H4 Conformational restraint 151 H5 Extra binding interactions H6 Enhancing existing binding interactions Section I- Pharmacokinetic orientated drug design 167 I1 Section- Patenting and manufacture 177 J2 Optimization of reactions J3 Scale-up issues J4 Process devek 193 Section K-Preclinical testing and clinical trials 1 Toxicology K2 Pharmacology and pharmaceutical chemistry K3 Drug metabolism studies K4 Clinical trials 212 216 Section L-Case study: inhibitors of EGF-receptor kinase LI Epidermal growth factor receptor Testing pre 224 L3 From lead compound to dianilino-phthalimides A Modeling studies 5 4-(Phenylamino)pyrrolopyrimidine 239 6. Pyrazolopyrimidines 241 Section M - History of medicinal chemistry M1 The age of herbs, potions and magic M3 A fledgling science (1900-1930 M4 The dawn of the antibacterial age(1930-1945 M5 The antibiotic age (1945-1970s M6. The age of reason(1970s to present) Further reading Index
ABBREVIATIONs AMP adenosine monophosphate HBD hydrogen bond donor 6-APA 6-aminopenicillanic acid HPLC ATP adenosine triphosphate chromatography IND Investigational Exemption to a DAG diacylglycerol New Drug Application deoxyribonucleic acid inositol trisphospl DMSO dimethylsulfoxide intravenous epidermal growth factor MAOI monoamine oxidase inhibitor EGF-R. epidermal growth factor mRNA Messenger RNA ece New Drug Application enzyme-bound product NMR nuclear magnetic resonance ES enzyme-substrate(complex) phosphatidylinositol FDA and Drugs agend GABA y-aminobutyric acid phospholipase C good clinical practice OSAR itive structure-activity GDP sine diphosphate GL good laboratory practice RNA ribonucleic acid GMP good manufacturing practice TRNA ribosomal RNA guanosine triphosphate SAR structure-activity relationship HBA hydrogen bond acceptor RNA
PREFACE This textbook provides a comprehensive set of basic notes in medicinal chemistry, which will be suit- able for undergraduate students studying a module in medicinal chemistry as part of a science, phar- macy or medical course. The book concentrates on the fundamental principles of medicinal chemi ind assumes no more than an elementary background of chemistry or biology It also serves as a useful first dipinto the subject for those students wishing to study medicinal chemistry itself Medicinal chemistry is an exciting new science, which has only come of age in the last 10-20 years It is a truly multidisciplinary subject involving such subject specialties as organic chemistry, pharma cology, biochemistry, physiology, microbiology, toxicology, genetics and computer modeling.Indeed most pharmaceutical companies organize research teams in such a way that scientists of different lisciplines interact with each other on a daily basis in order to fight the battle against disease. The very breadth of knowledge required by a medicinal chemist is both a challenge and a reward. Mastering an understanding of such a breadth of subject areas is no straightforward task, but by the same token there is ample intellectual stimulation in understanding the battle against disease at the molecular level and in designing molecular 'soldiers' to win that battle. This book attempts to condense the essentials of medicinal chemistry into a manageable text,which student friendly and does not cost an arm and a leg. It does this by concentrating purely on the basics of the subject without going into exhaustive detail or repetitive examples. Furthermore keynotes at the e Medicinal chemistry is a peculiar subject in that it feeds off so many other subjects. Understanding rt of each topic summarize the essential facts covered and help focus the mind on the essentials disease at the physiological, cellular and molecular levels is crucial if one is to design a suitable drug, and therefore knowledge of the relevant physiology, biochemistry, and pharmacology is of immense aid. However, the rapid advances made in two particular scientific areas are worth emphasizing Molecular biology and genetic engineering have produced a deluge of potential new targets for drug design and have unraveled the structures and mechanisms of traditional targets, while advances in computers and computer aided design have allowed medicinal chemists to take full advantage of thi newly earned knowledge Subsequent sections then follow the idenitabe n introduction to the science of medicinal chemistry The first four sections of this book serve stages that have to be negotiated by any date on its journey from initial brainstorm to the market place- a journey which takes many years and will see you graduated before it is! There are many difficult hurdles for the novice drug to over- come. The drug has to be ' so that it recognizes a specific target in the body and does not go fly- ingoffattacking' all and sundry. It has to gain access to the target by being absorbed into the blood upply, and in doing so it must be sturdy enough to ward off the many attacks that will be made on it by the bodys defenses. It must also be controlled in its'aggression', being a mild and harmless visitor during most of its body tour, but ruthless and efficient when it reaches its target. Designing such char acteristics is not: straightforward and a drugs behavior involves many tests and trials, both in the lab and in the clinic before it comes of age It is hoped that students will find this textbook useful in their studies and that once they have gra what medicinal chemistry is all about, they will read more widely and enter this truly exciting of molecular medicine
ABOUT THE AUTHOR Graham Patrick studied chemistry at Glasgow University where he gained a BSc Honours(1st)and won the Mackay Smith prize. He was awarded a Carnegie scholarship and successfully completed a PhD degree on the biosynthesis of gliotoxin. Since then he has held postdoctoral research posts at Strathclyde University and the Australian National University, and has had industrial experience working with pharmaceutical firms such as Glaxo, Beechams, and Organon Pharmaceuticals. He lectured at the chemistry at Paisley University, where he is also the course leader for medicinal chemistry medicinal Department of Chemistry at Leeds University and is currently lecturing in chemistry and medicinal Dr Patrick has written several undergraduate textbooks including An Introduction to Medicinal Chemistry(2nd edition, 2001, Oxford University Press), two self-learning texts on basic organic chem- stry, and Instant Notes in Organic Chemistry(BiOS Scientific Publishers Ltd. 2000). He has several esearch publications in the area of organic synthesis, medicinal chemistry and bio-organic chemistry, and has also written several reviews. His current research interests are the design and synthesis of novel antifungal and antimalarial agents Recently, he has collaborated with the Borders Educational Council of Scotland in the production of video and CD lectures covering aspects of medicinal chemistry for school courses
Section A- The science of medicinal chemistry A1 INTRODUCTION Key Notes Medicinal chemistry is the design and synthesis of novel drugs, based on an understanding of how they work at the molecular level. A useful drug must interact with a molecular target in the body (pharmacodynamics and also be capable of reaching that target(pharmacokinetics). A medicinal chemist is skilled in the fields of organic synthesis, molecular modeling and drug design, and should have a basic knowledge of relevant subjects such as biochemistry and pharmacology E Drug Drugs are normally low molecular weight chemicals that interact with macromolecular targets in the body to produce a pharmacological effect That effect may be beneficial or harmful depending on the drug used and he dose administered Classifications of Drugs can be classified according to their pharmacological effect, the drugs particular biochemical process they affect, the type of structures they are, or the molecular target with which they interact. The last classification is the most useful one in medicinal chemistry Related topic From concept to market(A2) Medicinal The science of medicinal chemistry involves the design and synthesis of novel drugs based on an understanding of how drugs work in the body at the molec- ular level. There are two major considerations that have to be considered in any drug design project. First of all, drugs interact with molecular targets in the body, and so it is important to choose the correct tar ceutical effect. It is then a case of designing a dne, get for the desired pharma- hat will interact as fully and selectively as possible for that target-an area of medicinal chemistry known as rhan dynamics. Drug targets will be discussed in more detail in Section B. Secondly, a drug has to travel through the body in order to reach its target, so it is important to design the drug so that it is able to carry out that journey. This is an area known as pharmacokinetics and is discussed in Section Medicinal chemistry has come of age in the last 20 years. Before that, advances were often made as a result of trial and error, intuition or pure luck Large numbers of analogs were synthesized based on the structure of a known active compound (defined as the lead compound), but little was known about the detailed mechanism of drug action or the structures of the targets with which they interacted. Advances in the biological sciences have now resulted in a much better understanding of drug targets and the mechanisms of drug action. As a result, drug design is as much"target oriented as 'lead compound
Section A- The science of medicinal chemistry The medicinal Medicinal chemistry is an interdisciplinary science that, by its very nature, chemist encompasses the sciences of chemistry, biochemistry, physiology, pharma- cology, and molecular modeling, to name but a few. a good understanding of these subject areas is useful, but it is unlikely that any one person could be naster of all. Thus, the pharmaceutical industry relies on multidisciplinary teams of scientists who are specialists in their own fields and can work together structures required. Therefore, the medicinal chemist is an essential member of any drug design team since he or she has to identify whether proposed target structures are likely to be stable and whether they be synthesized or not. Traditionally, the pharmaceutical industry has recruited graduates with a chem- istry degree since this is the best method of acquiring the synthetic organic chemistry skills required for medicinal chemistry. However, it is often the case that graduates with a conventional chemistry degree have little background in the biological sciences and have had to acquire that background on the job. In recent years, many universities have started to offer medicinal chemistry degrees that are specifically designed to prepare chemistry graduates for the pharmaceutical industry. Such degrees contain the important core topics required for a conventional chemistry degree (i.e. physical, inorganic and organic chemistry), but also include topics such as drug design, pharmacology, molecular modeling, combinatorial synthesis, bio-organic and bio-inorganic Drugs are chemicals that are normally of low molecular weight(-100-500)and which interact with macromolecular targets to produce a biological response That biological response may be therapeutically useful in the case of medicines, or harmful in the case of poisons. Most drugs used in medicine are potential isons if taken in doses higher than those recommended Classifications There are several ways in which drugs can be classified. First, drugs can be of drugs classified according to their pharmacological effect- for example, analgesics are drugswhich have a pain-killing effect. This classification is useful for doctors wishing to know the arsenal of drugs available to tackle a particular problem, but it is not satisfactory for a medicinal chemist as there are many different targets and mechanisms by which drugs can have an analgesic effect. Therefore it is not possible to identify a common feature which is shared by all analgesics For example, aspirin and morphine act on different targets and have no struc- tural relationship(Fig. 1). Other examples of drugs that are classified in this way
A1-Introduction are antidepressants, cardiovascular drugs, anti-asthmatics, and anti-ulcer second, drugs can be classified depending on whether they act on a particular biochemical process. For example, antihistamines act by inhibiting the action of the inflammatory agent histamine in the body. Although this classification is more specific than the above, it is still not possible to identify a common feature relating all antihistamines. This is because there are various ways in which the action of histamine can be inhibited. Other examples of this kind of classification are cholinergic or adrenergic drugs a third method of classifying drugs is by their chemical structure (Fig. 2) Drugs classified in this way share a common structural feature and often share a similar pharmacological activity. For example, penicillins all contain a B-lactam ring and kill bacteria by the same mechanism. As a result, this classification can sometimes be useful in medicinal chemistry. However, it is not foolproof. Sulfonamides have a similar structure and are mostly antibacterial. However, some sulfonamides are used for the treatment of diabetes. Similarly steroids all have a tetracyclic structure, but the pharmacological effect of different steroids can be quite different. H CHa CO2H Steroids Fg. 2. Drugs classified by structure Finally, classifying drugs according to their molecular target is the most useful classification as far as the medicinal chemist is concerned since it allow a rational comparison of the structures involved. For example, anticholin esterases are compounds that inhibit an enzyme called acetylcholinesterase They have the same mechanism of action and so it is valid to compare the various structures and identify common features
Section A-The sclence of medicinal chemistry A2 FROM CONCEPT TO MARKET Key Notes In general, there are three main phases in getting a drug to the market drug discovery, drug design and drug testing/development ise1-drug Most medicinal chemistry projects start by identifying a drug target.A discovery is then developed and a search is made for compound having the desired activity-a lead compound Phase 2-drug Analogs of the lead compound are synthesized and tested, allowing identification of structural features which are important for activity. These features are retained during the design of analogs with improved pharmacodynamic and pharmacokinetic properties and deverug testing Drugs are patented as quickly as possible. Pre-clinical trials are carried elopment out to assess the properties and safety of the new drug. If these pre atisfactory, clinical trials are carried out. The development of a large cale synthesis proceeds in parallel to the biological testing Regulatory authorities are responsible for approving drugs for clinical trials and the The chemist's A graduate with a chemistry or medicinal chemistry degree has skills industry, such as drug discovery, drug design, quality control, radiosynthesis and manufacture Related topic Introduction(Al) verview In general, there are three phases involved in discovering a new drug and getting it to market. Phase 1 is drug discovery, which involves finding an active compound for a particular target. Phase 2 is drug design, where the propertie of that active compound are improved such that it is potent and selective for its target and can also reach that target. Phase 3 involves all the testing procedures and development work that have to be carried out on the drug in order to get it to the market Phase 1-drug Nowadays, most medicinal chemistry projects start by identifying a suitable discovery drug target(Section B). Knowledge of the physiological role played by that target allows the researcher to propose what effect a drug would have if it inter acted with the target. Drug targets are usually biological macromolecules such as carbohydrates, lipids, proteins and nucleic acids. The most common targets are proteins followed by nucleic acids. Once a target has been chosen, suitable testing methods have to be developed (Section D) which will demonstrate whether potential drugs have the desired activity. It is then a case of finding a
