DAVID MANALLACK: In this module, a drug side effect was the spark that led to the development of drugs to treat high levels of glucose in the blood, or hyperglycemia.
When diet and exercise are insufficient to control diabetes, as in Shirley’s case, we can explore the use of medicines to help control her condition. Our story begins in the 1930s, as a French research team discovered that the metabolite of the newly discovered antibiotic, prontosil, was the active agent that fought bacteria. This metabolite is known as sulfanilamide. The structure is relatively simple, comprising a benzene ring with an amino group and a sulfonamide group.
Given that sulfanilamide was a poorly active antibiotic with low solubility, numerous analogues of this substance were made and tested. Typically, this involved adding an aromatic ring to the sulfonamide nitrogen atom. Amongst these improved antibiotics was a compound known only as IPTD, which was used to treat typhoid fever. Use IPTD, however, tragically led to a number of deaths, caused by severe hypoglycemia, or low blood sugar. Further work in the 1940s determined that IPTD was stimulating the pancreas to release more insulin. Putting two and two together, the student who discovered this effect suggested that IPTD could be used to treat diabetes. Sadly, this largely fell on deaf ears.
As France fell to Germany in the Second World War, the research into IPTD was taken over by a German pharmaceutical firm, Chemische Fabrik von Heyden. They looked at other sulfonamide drugs and found that carbutamide had the same hypoglycemic effect. A quick look at the structure of carbutamide reveals that the ring on the right-hand side has been replaced by a short chain of carbon atoms. Indeed, this hydrophobic group on the right has now become an established feature of this class of drugs.
At the end of World War II, and as the company was based in Dresden, it then became part of East Germany and disappeared behind the Iron Curtain. In 1952, a sample of carbutamide was smuggled into West Germany. The Iron Curtain had been breached, and carbutamide was briefly used as a medicine in the 1950s in West Germany. This was short lived, as carbutamide was found to produce fatal side effects in a very small number of people, and the drug was, therefore, discontinued. The next development in this field produced tolbutamide.
The difference in their structures was quite subtle. The amino group on the benzene ring was replaced with a methyl group, and this managed to greatly reduce the toxicity of the compound. On the downside, it was quickly metabolised and had to be taken twice a day. Again, chemistry stepped in to try and solve this problem. As the methyl group on the benzene ring of tolbutamide is a site of metabolism, medicinal chemists replaced this methyl group with a chlorine atom in chlorpropamide. This managed to greatly reduce metabolism, and the drug was no longer cleared as quickly from the body. Once a day dosing was now possible, which provided a convenience to patients. Chlorpropamide, however, is not widely used anymore.
You will also notice that the carbon chain on the right-hand side of the molecule has been reduced by one carbon atom. Well, let’s have a look at the structure of chlorpropamide. The chemists knew that changes could be made to the groups attached to the left-hand side of the ring and to the hydrophobic groups on the right. The central section of this drug, highlighted in red, is called a sulfonylurea. And this name is applied to this general class of antidiabetic agents.
Leaving the benzene ring and sulfonylurea group alone, medicinal chemists have made more radical changes to these compounds in efforts to make better drugs. In this example, we can see that the left-hand side has been changed dramatically. From the simple variation of an amino group to a methyl group and also to a chlorine atom, we now have a very large group with an aromatic ring.
Glibenclamide provided the idea that there was a lot of scope to vary the molecule on the left-hand side. To medicinal chemists, this indeed was a great advantage. They could leave the sulfonylurea and benzene ring alone to get the biological activity they wanted, that is an increase of the release of insulin from the pancreas, while letting them play with the left and right-hand sides to achieve the right profile. And the profile they were after was one which provided good potency with the right characteristics to be a drug. In other words, it has to be safe, effective, and convenient for clinical use.
While glibenclamide wasn’t perfect, given that there was variation in the metabolism from person to person, it led to gliclazide, which emerged in the 1980s. In the following article, we will take you through the next generation of sulfonylurea drugs.