The development of the anti-peptic ulcer drug cimetidine gives a fascinating insight into the important role of pKa in chemistry. Peptic ulcers are a localized erosion of the mucous mem brane, resulting from overproduction of gastric acid in the stomach. One of the compounds that controls the production of the acid is histamine. (Histamine is also responsible for the symptoms of hay fever and allergies.)

Histamine works by binding into a receptor in the stomach lining and stimulating the pro duction of acid. What the developers of cimetidine at Smith, Kline and French wanted was a drug that would bind to these receptors without activating them and thereby prevent hist amine from binding but not stimulate acid secretion itself. Unfortunately, the antihistamine drugs successfully used in the treatment of hay fever did not work—a different histamine receptor was involved. Notice that cimetidine and histamine both have the same nitrogen-containing ring (shown in black) as part of their structures. This ring is known as an imidazole—imidazole itself is quite a strong base whose protonated form is delocalized as shown below. This is not coincidence—cimetidine’s design was centred around the structure of histamine.

In the body, most histamine exists as a salt, being protonated on the primary amine and the early compounds modelled this. The guanidine analogue was synthesized and tested to see if it had any antagonistic effect (that is, if it could bind in the histamine receptors and prevent histamine binding). It did bind but unfortunately it acted as an agonist rather than an antagonist and stimulated acid secretion rather than blocking it. Since the guanidine analogue has a pKa even greater than histamine (about 14.5 compared to about 10), it is effectively all proto-nated at physiological pH

The agonistic behaviour of the drug clearly had to be suppressed. The thought occurred to the chemists that perhaps the positive charge made the compound agonistic, and so a polar but much less basic compound was sought. Eventually, they came up with burim amide. The most important change is the replacement of the C=NH in the guanidine compound by C=S. Now instead of a guanidine we have a thiourea, which is much less basic. Other adjustments were to increase the chain length, insert a second sulfur atom on the chain, and add methyl groups to the thiourea and the imidazole ring, to give metiamide with increased efficacy.

The new drug, metiamide, was ten times more effective than burimamide when tested in humans. However, there was an unfortunate side-effect: in some patients: the drug caused a decrease in the number of white blood cells, leaving the patient open to infection. This was eventually traced back to the thiourea group. The sulfur had again to be replaced by oxygen, to give a normal urea and, just to see what would happen, by nitrogen to give another guanidine.

Neither was as effective as metiamide but the important discovery was that the guanidine analogue no longer showed the agonistic effects of the earlier guanidine. Of course, the guani-dine would also be protonated so we had the same problem we had earlier—how to decrease the pKa of the guanidinium ion. A section of this chapter considered the effect of electron withdrawing groups on pKa and showed that they make a base less basic. This was the approach now adopted—the introduction of electron-withdrawing groups on to the guanidine to lower its pKa. The table below shows the pKas of various substituted guanidinium ions.

Clearly, the cyano and nitro-substituted guanidines would not be protonated at all. These were synthesized and found to be just as effective as metiamide but without the side-effects. Of the two, the cyanoguanidine compound was slightly more effective and this was developed and named ‘cimetidine’.

The development of cimetidine by Smith, Kline and French from the very start of the project up to its launch on the market took 13 years. This enormous effort was well rewarded—Tagamet (the trade name of the drug cimetidine) became the best-selling drug in the world and the fi rst to gross more than one billion dollars per annum. Thousands of ulcer patients worldwide no longer had to suffer pain, surgery, or even death. The development of cimetidine followed a rational approach based on physiological and chemical principles and it was for this that one of the scientists involved, Sir James Black, received a share of the 1988 Nobel Prize for Physiology or Medicine. None of this would have been possible without an understanding of pKas.

مواضيع ذات صلة

Organometallics as bases

How to make organolithium reagents

Making organometallics, How to make Grignard reagents

Organometallic compounds contain a carbon–metal bond

Lewis acids and bases

Why do we need to compare acid strengths of O and N acids?

Carbon acids

Substituents affect the pKa

The ‘pKas’ of bases

Nitrogen compounds as acids and bases

Delocalization of the negative charge stabilizes the conjugate base

Constructing a pKa scale