8 minutes reading time (1654 words)

    The Discovery of Ventolin

    Peter O'Brien
    The University of York

    Asthma is a very common disease, affecting one person out of every 20. So, if you are not asthmatic, it is highly likely that you know someone who is. indeed, you have probably seen people using medication for asthma in the form of an inhaler. The usual symptoms of asthma are wheezing and breathlessness which makes it a distressing disease. Acute asthma attacks lead to about 1,800 deaths per year in Britain alone. However, if controlled using modern day drugs, it is possible for asthma sufferers to lead normal, long and healthy lives. For example, according to the National Asthma Campaign a host of sportsmen and women suffer from asthma. Probably the best known sportsman of recent times is the Manchester United and England footballer Paul Scholes who uses two different inhalers to control his asthma depending on whether it is a match day or not!

    There is currently no cure for asthma, as the complex mechanisms in the body which trigger the symptoms are far from being understood. However, it is possible to treat the symptoms which are caused by the airways in the lungs (known as the bronchi) becoming narrowed and inflamed. In order to relieve the asthma attack, the narrowed airways need to be opened and it is in this way that the drugs in this article operate.

    Such drugs are called bronchodilators as they dilate (widen) the bronchi (airways). Drug compounds (eg. aspirin, paracetamol etc.) are in general relatively simple organic molecules which work by becoming attached to part of a cell in our bodies (a receptor) and interacting with the cells as to initiate a response. In the case of bronchodilators, the response is relaxation of the smooth muscle tissue resulting in widening of the airways. 

    A breath of fresh air for asthma sufferers

    In 1969, Glaxo (now called GlaxoWellcome) launched a product called Ventolin, which delivers a bronchodilator drug via an inhaler. The drug molecule in Ventolin is the organic compound salbutamol (see Figure 1). Salbutamol is extremely effective for the treatment of asthma symptoms and even today, 30 years on, the drug is still in use. But just how did chemists at Glaxo discover that salbutamol had the correct collection of carbon, hydrogen, nitrogen and oxygen atoms for treating asthma? It is this process of drug discovery that we will follow for salbutamol in this article. (For a general outline of the process of discovering and developing a drug compound, see Box 1.)

    Drug discovery and salbutamol

    The discovery process for any new drug requires the combined efforts of chemists, biochemists and biologists. The salbutamol programme was no different and the important stages at the start of its discovery were as follows. First of all, it was necessary to identify the chemical compound in nature that was responsible for keeping the airways open (i.e. nature's own bronchodilator) and to determine its chemical structure. Next, parts of the chemical structure of the natural bronchodilator were modified by chemists and the effect these changes had on relaxing smooth muscle tissue was assessed by biologists. Some of the changes led to desirable effects but others produced unwanted side effects. Then, this process of modification was repeated hundreds of times in order to find the single organic compound that had the best level of muscle-relaxing activity with the least side effects. As described in Box 1, this modification stage of a drug discovery programme typically extends for some 4-5 years.

    Adrenaline's role in the drug discovery

    The organic compound responsible for keeping our airways open is adrenaline. It is released in the body by the adrenal glands when we are frightened or excited or feel the need to act quickly. Adrenaline was the starting point in the drug discovery programme (its chemical structure is shown in Figure 2). A quick glance at the chemical structures of salbutamol (Figure 3) and adrenaline (Figure 2) reveals that they are in fact very similar. Can you spot the differences?

    So what happens when we use adrenaline as our starting point and change parts of its chemical structure? Before we answer that, it is necessary to address a question that you may have at this stage. lf adrenaline is nature's own bronchodilator, why not give asthma sufferers more of this compound to open the airways? In other words, why not use adrenaline as our asthma drug? This is an excellent suggestion, but unfortunately, as well as opening the airways, adrenaline has other roles in our bodies. For example, adrenaline also leads to excessive stimulation of the brain, a faster beating heart and an increase in blood pressure, all of which are highly undesirable side effects for a drug compound. What we need for our ideal drug is a compound similar in chemical structure to adrenaline which functions as a bronchodilator but does not have any bad side effects.

    From adrenaline to salbutamol

    To discover an asthma drug related to adrenaline, we need to look closely at the chemical structure of adrenaline. It has five different structural fragments suitable for modification (see Figure 3): the two phenolic hydroxyl groups (1), the benzene ring (2), the secondary hydroxyl group (3), the secondary amino group (4) and the substituent on the amino group (5). Changing any of these five parts could lead to a better drug candidate for the treatment of asthma (or of course to a far worse compound). Parts of organic molecules are changed using the methods of organic synthesis, namely the construction of the required compounds from cheap and commercially available building blocks (see Box 2). There are many ways in which parts of organic molecules can be changed. For example, it is possible to remove groups altogether, to change the size of substituents or to change the electronic properties of groups (eg. by swapping an electron donating substituent for an electron withdrawing substituent). It is also possible to add or remove hydrogen bonding groups such as hydroxyl groups. The key question is where to start with a molecule such as adrenaline. 

     Knowledge of the biological mode of action of adrenaline suggested that changing the substituent on the amino group (5) could lead to improved properties. Thus, isoprenaline (see Figure 4) was prepared and tested. By changing the nitrogen substituent from a small methyl (CH3) group to a larger isopropyl (CH(CH3)2) group, the side effect of increased blood pressure was removed without affecting the beneficial bronchodilator effects. However, isoprenaline still produced increased heart rates and it was not a very long-lasting drug since it was broken down (metabolised) by enzymes in the body.

    Such enzymes work by interacting with on of the two phenolic hydroxyl groups (1) and so this part of isoprenaline was modified next. The resulting compound, adrenaline diol (Figure 5), only had one phenolic hydroxyl group but was completely ineffective as a bronchodilator. This was believed to be because the methyl ester group in the adrenaline diol could not participate in hydrogen bonding. Replacing this group with a hydroxyl group that could hydrogen bond but that crucially was not directly bonded to the benzene ring (and so was not broken down by the enzymes in the body) gave adrenaline triol (Figure 4). Adrenaline triol had all of the effective asthma-relieving properties, few side effects and was long lasting (up to about 4 hours).

    Although long lasting, adrenaline triol still had the unwanted side effect of increasing the heart rate and so one final change was made. The nitrogen substituent was increased in size from an isopropyl (CH(CH3)2) group to the very large tert-butyl (C(CH3)3) group to give the compound salbutamol (Figure 4). Salbutamol, marketed as Ventolin and best given by inhalation from an aerosol, is a very good bronchodilator with practically no side effects and, as with adrenaline triol, lasts for up to 4 hours.

    To put the modification stage of the drug discovery process that we have just discussed into context, it is worth mentioning that Figure 4 provides only a very brief overview the structural changes that were made by the researchers at Glaxo. In reality, well over 100 compounds were made and tested. And, using the methods of organic synthesis (see Box 2), it probably took a group of research chemists about 1 week of laboratory work to prepare each one of these compounds. Thus, the synthesis of 100 different compounds required 2 years of hard labour in the laboratory! 

    A final note

    Salbutamol has proved to be a very effective drug for the treatment of asthma. However, since its effects last for a maximum of 4 hours, asthma sufferers often find themselves waking up in the middle of the night with an attack as the effect of the drug wears off. With this in mind, the researchers at Glaxo went back to the drawing board and began the whole process of drug discovery once again but this time used salbutamol as the starting point in place of adrenaline. Eventually, it was found that a more drastic change to the nitrogen substituent produced salmeterol (Figure 4), an effective bronchodilator with a duration of action of about 12 hours. Salmeterol, marketed as Serevent and also taken by inhalation, is now available but salbutamol is still the drug of choice for acute attacks.

    With salbutamol and the recent marketing of salmeterol, GlaxoWellcome has a strong portfolio of drug compounds in the asthma area and it currently has a very active research team looking into the discovery of new drugs for treating the disease. Hopefully this article has demonstrated the singularly important role of chemistry in the discovery and development of drug compounds.

    About the author
    Peter O'Brien obtained his PhD from the University of Cambridge in 1995. In March 1996, he was appointed to a lectureship at The University of York. He is currently a lecturer in organic chemistry in the Department of Chemistry where his research group is developing new methods in synthetic organic chemistry.
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