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