Medicinal Chemistry IIInd Module
Drug discovery, design and development
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Drug discovery, design and development: the pastBefore the twentieth century, medicines consisted mainly of herbs and potions and it was not until the mid-nineteenth century that the first serious efforts were made to isolate and purify the active principles of these remedies (i.e. the pure chemicals responsible for the medicinal properties). The success of these efforts led to the birth of many of the pharmaceutical companies we know today. Since then, many naturally occurring drugs have been obtained and their structures determined (e.g. morphine from opium, cocaine from coca leaves, quinine from the bark of the cinchona tree).These natural products sparked off a major synthetic effort where chemists made literally thousands of analogues in an attempt to improve on what nature had provided. Much of this work was carried out on a trial and error basis, but the results obtained revealed several general principles behind drug design. Many of these principles will be described.An overall pattern for drug discovery and drug development also evolved, but there was still a high element of trial and error involved in the process.The mechanism by which a drug worked at the molecular level was rarely understood, and drug research focused very much on what is known as the lead compound: an active principle isolated from a natural source or a synthetic compound prepared in the laboratory.
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Drug discovery, design and development: the present
In recent years, medicinal chemistry has undergone a revolutionary change. Rapid advances in the biological sciences have resulted in a much better understanding of how the body functions at the cellular and the molecular level. As a result, most research projects in the pharmaceutical industry or university sector now begin by identifying a suitable target in the body and designing a drug to interact with that target. An understanding of the structure and function of the target, as well as the mechanism by which it interacts with potential drugs is crucial to this approach.Generally, we can identify the following stages:
Drug discovery: finding a lead Drug design Drug development
Many of these stages run concurrently and are dependent on each other. For example, preclinical trials are usually carried out in parallel with the development of a manufacturing process. Even so, the discovery, design and development of a new drug can take 15 years or more, involve the synthesis of over 10000 compounds, and cost in the region of $800 million.
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Drug discovery: finding a lead
Choose a disease!
Choose a drug target.
Identify a bioassay.
Find a 'lead compound'.
Isolate and purify the lead compound if necessary.
Determine the structure of the lead compound if necessary.
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Identify structure-activity relationships (SARs).
Identify the pharmacophore.
Improve target interactions (pharmacodynamics).
Improve pharmacokinetic properties.
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Patent the drug.
Carry out preclinical trials (drug metabolism, toxicology, formulation and stability tests, pharmacology studies etc).
Design a manufacturing process (chemical and process development).
Carry out clinical trials.
Register and market the drug.
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Choosing a diseaseHow does a pharmaceutical company decide which disease to target when designing a new drug? Clearly, it would make sense to concentrate on diseases where there is a need for new drugs. However, pharmaceutical companies have to consider economic factors as well as medical ones. A huge investment has to be made towards the research and development of a new drug. Therefore, companies must ensure that they get a good financial return for their investment. As a result, research projects tend to focus on diseases that are important in the developed world, because this is the market best able to afford new drugs. A great deal of research is carried out on ailments such as migraine, depression, ulcers, obesity, flu, cancer, and cardiovascular disease. Less is carried out oil the tropical diseases of the developing world. Only when such diseases start to make an impact on western society do the pharmaceutical companies sit up and take notice. For example, there has been a noticeable increase in antimalarial research as a result of the increase in tourism to more exotic countries, and the spread of malaria into the southern states of the USA.Choosing which disease to tackle is usually a matter for a company's market strategists.
The science becomes important at the next stage!
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Choosing a drug targetOnce a therapeutic area has been identified, the next stage is to identify a suitable drug target (e.g. receptor, enzyme, or nucleic acid). An understanding of which biomacromolecules are involved in a particular disease state is clearly important. This allows the medicinal research team to identify whether agonists or antagonists should be designed for a particular receptor, or whether inhibitors should be designed for a particular enzyme. For example, agonists of serotonin receptors are useful for the treatment of migraine and antagonists of dopamine receptors are useful as antidepressants. Sometimes it is not known for certain whether a particular target will be suitable or not. For example, tricyclic antidepressants such as desipramine are known to inhibit the uptake of the neurotransmitter noradrenaline from nerve synapses by inhibiting the carrier protein for noradrenaline. However, these drugs also inhibit uptake of a separate neurotransmitter called serotonin, and the possibility arose that inhibiting serotonin uptake might also be beneficial. A search for selective serotonin uptake inhibitors was initiated, which led to the discovery of the best-selling antidepressant drug fluoxetine (Prozac), but when this project was initiated it was not known for certain whether serotonin uptake inhibitors would be effective or not.
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Discovering drug targetsIf a drug or a poison produces a biological effect, there must be a molecular target for that agent in the body. In the past, the discovery of drug targets depended on finding the drug first. Many early drugs such as the analgesic morphine are natural products derived from plants, and just happen to interact with a molecular target in the human body. As this involves coincidence more than design, the detection of drug targets was very much a hit and miss affair. Later, the body's own chemical messengers started to be discovered and pointed the finger at further targets. For example, since the 1970s a variety of peptides and proteins have been discovered which act as the body's own analgesics (enkephalins and endorphins). Despite this, relatively few of the body's messengers were identified, either because they were present in such small quantity or because they were too short lived to be isolated. Indeed, many chem- ical messengers still remain undiscovered today. This in turn means that many of the body's potential drug targets remain hidden. Or at least it did! The advances in genomics and proteomics have changed all that. The various genome projects which have mapped the DNA of humans and other life forms, along with the newer field of proteomics (section 2.6), are revealing an ever increasing number of new proteins which are potential drug targets for the future, These targets have managed to stay hidden for so long that their natural chemical messengers are also unknown and, for the first time, medicinal chemistry is faced with new targets, but with no lead compounds to interact with them. Such targets have been defined as orphan receptors. The challenge is now to find a chemical which will interact with each of these targets in order to find out what their function is and whether they will be suitable as drug targets, 'I his has been one of the main driving forces behind the rapidly expanding area of combinatorial synthesis.
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Recently discovered target: the caspasesThe caspases are examples of recently discovered enzymes that may prove useful as drug targets. They are a family of protease enzymes, which catalyse the hydrolysis of important cellular proteins, and which have been found to play a role in inflammation and cell death. Cell death is a natural occurrence in the body, and cells are regularly recycled. Therefore, caspases should not necessarily be seen as 'bad' or 'undesirable' enzymes. Without them, cells could be more prone to unregulated growth resulting in diseases such as cancer.The caspases catalyse the hydrolysis of particular target proteins such as those Involved in DNA repair, and the regulation of cell cycles. By understanding how these enzymes operate, there is the possibility of producing new therapies for a variety of diseases. For example, agents which promote the activity of caspases and lead to more rapid cell death might be useful in the treatment of diseases such as cancer, autoimmune disease, and viral infections. Alternatively, agents that inhibit caspases and reduce the prevalence of cell death could provide novel treatments for trauma, neurodegenerative disease, and strokes. It is already known that the active site of caspases contains two amino acids that are crucial to the mechanism of hydrolysis: cysteine, which acts as a nucleophile, and histidine, which acts as an acid-base catalyst. The mechanism is similar to that used by acetyl