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