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Before discussing any one disease or family of drugs in much depth, it’s worth having a look at the method used by pharmaceutical companies to develop drugs.

Mankind has been using plants extracts as medicine for a long time.

During the mid 19th century, people started trying to isolate the active compounds within these plants- the molecules responsible for the medicinal qualities.

This was the beginning of the pharmaceutical industry.

Picture: Clip Art

Drug Companies work on the basis of expected return for their investment. So, sadly, when they identify a disease to try to cure, it is not usually going to be a disease attacking the developing world where people do not have much money.

 When you have a look at the rate of success in drug development, the reasons behind this mercenary attitude become a little clearer: 

  • For every 10 000 molecules investigated for possible medicinal qualities, only 10 reach clinical trials and only 1 of those may be made available for patients.
  • The average overall development cost for a new drug is estimated to be over NZ$800 million at current exchange rates (GBP £444 million).
  • Average time to develop a drug is 10-15 years

Once a disease has been chosen, the next step is to identify a suitable drug target. This is where it is very important to understand how the disease works and what is going on in the body.

Typically, a drug target is one of the following three parts of the body that is involved in the disease.

  • Receptor (a protein on a cell surface, allows chemical messengers into the cell)
  • Enzyme (act as catalysts to make biological reactions happen easier)
  • Nucleic acid (part of DNA)

Thousands of molecules are then screened to choose a lead compound. This is a molecule that interacts with the drug target in a therapeutic way to help control the disease.

Chemistry comes to the fore now as lots of variations of this lead compound are made. These different compounds are then analysed to discover which will control the target disease safely.

Having discovered the best compound to act as your drug, the next step is to make sure the drug will reach its target in the body.

Drugs need to be absorbed into the blood, to reach their target efficiently, to be stable enough to survive the journey, and to be excreted within a reasonable length of time.

Again, chemistry is used to manipulate the properties of the chosen compound to get this to happen.

Before this drug hits the market, there are still many different issues to deal with:

  • patents,
  • pre-clinical trials,
  • three stages of clinical trials
  • on-going studies to monitor the long-term effects of this drug
  • registration and approval from the Food and Drug Administation in the United States.

  

Drug Development: An Example

Identified disease: Asthma.

Disease background: Asthma is when lung bronchi (airways) become narrower. When faced with certain triggers, these airways may partially close up, swell or make more mucous and become clogged up.

This can cause difficulty in breathing, a feeling of tightness in the chest, coughing and wheezing. Severe asthma can cause death.

Diagram: United States Federal Government (Wikipedia Commons)
 

Chosen drug target: Beta-2 Adrenoreceptor.

There are several different types of receptors in the body that are activated or ‘turned on’ by a molecule of adrenaline reaching them.

Adrenaline activates Beta-2 receptors. This causes smooth muscles to relax. Relaxing the smooth muscles in the bronchi will widen the airways, which helps a person suffering from asthma to breathe easier.

Lead compound: Adrenaline.

Adrenaline itself was one of the first compounds used to help in asthma attacks.

It produces short-term relaxation of the airways but it also stimulates a lot of other types of adrenergic receptors, leading to many side-effects including heart problems.

Developed drug compound: Salbutamol (trade name Ventolin).

Salbutamol is over 2000 times less active on the heart than adrenaline, meaning it produces fewer side effects.

The relaxing effect of Salbutamol on the smooth muscle of the bronchi lasts for 4 hours.

Interestingly, Salbutamol is a chiral compound, meaning that it is two non-superimposable mirror images.

For a simple example of chiral objects hold your hands out, palms facing away from you. Your hands are mirror images of each other. Try to get your hands to look exactly the same, top and bottom of the hands facing the same way and thumbs on the same side. It’s not possible: your hands are non-superimposable mirror images.

Both of these mirror image compounds (called R and S to distinguish them) were produced in the Salbutamol drug until it was recognised that the R-compound is 68 times more active than the S-compound.

The less-active S-compound is also the one held responsible for side effects. This resulted in production of pure R-salbutamol, called Levalbutarol (trade name Xopenex).

To summarise, the process of drug development process requires investment of a phenomenal sum of time and money. Return on investment currently holds great influence over which disease is chosen to design drugs for. The desperate need seen in developing countries for drugs to tackle tuberculosis (TB), malaria, sleeping sickness and other tropical diseases is largely ignored.

For more information, refer to:

Patrick, G. (2009) An Introduction to Medicinal Chemistry, 4th Ed., New York: Oxford University Press. Chapters 12-16, pages 595, 602, 603.

Asthma Foundation New Zealand’s webpage: http://www.asthmafoundation.org.nz/_6.php

UK Parliament web document on disease in developing countries and the need for new drugs: http://www.parliament.uk/documents/post/postpn241.pdf

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