Gastric acid in the stomach (primarily hydrochloric acid) is essential to digest protein and emulsify fats. It breaks down food so it can go on to the small intestines where nutrients are absorbed. Insufficient levels of gastric acid can contribute to a myriad of discomforts and diseases. On the other hand, too much of a good thing can also be problematic. High levels of gastric acid can contribute to heartburn and ulcers. Nowadays, physicians have a fancy name for this condition: gastroesophageal reflux disease (GERD).
If GERD results from too much acid in the stomach, there would appear to be a simple solution—neutralize the acid with an orally administered base. While this can work, it would require around 60 g of sodium bicarbonate (NaHCO3) a day to treat patients with gastric ulceration! Meanwhile, calcium-based antacids like Tums or Rolaids can occasionally contribute to kidney stones while aluminum- or magnesium-based antacids like Mylanta and Maalox can sometimes be dangerous for people with kidney problems.
The emergence of histamine-2 receptor antagonists in the 1980s revolutionized the treatment of GERD. The first drug of this type, cimetidine (Tagamet), was so successful that it is now considered by many to be the first “blockbuster” drug. The market success of cimetidine soon spawned additional drugs of the same type, such as ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid). Interestingly, altering the pKa of a key functional group was pivotal in the discovery of Tagamet and the later follow-on drugs.
In 1964, James Black, discoverer of the best-selling beta-blocker drug propranolol, led a group at SmithKline & French to pursue what he hoped would be a new class of drugs to treat stomach ulcers. These drugs would act directly to reduce stomach acid secretion by selectively antagonizing the histamine-2 (H2) receptor. Starting from the natural ligand histamine, the group synthesized and tested a variety of new analogs. Among the early analogs was 4-methyl-histamine, a compound that turned out to be an agonist of the receptor and therefore stimulated acid secretion rather than suppressing it! Undeterred, the group pressed on and eventually found that by replacing the methylamine in 4-methyl-histamine with a guanidine function, they could produce compounds such as guanylhistamine that started to show antagonist-like behavior (“partial antagonists”).
Unfortunately, guanylhistamine and related compounds were poorly absorbed from the stomach, most likely because they are strong bases and thus will be protonated (charged) in the acidic, gastric environment. Charged drug molecules can have trouble traversing the epithelial cells that line the small and large intestines, and across which drugs must pass to be orally absorbed. Further optimization of the H2-receptor antagonists would be required, both to improve potency and to increase oral absorption—possibly by altering the pKa of the guanidine function (reducing its basicity). Eventually, improved molecules like burimamide and metiamide were identified in which a weakly basic thiourea function replaced the much more basic guanidine function. Burimamide was the group’s first bona fide pure H2-antagonist without agonist effects, and was also active in animals. Metiamide was an even more potent antagonist and also had improved oral bioavailability. Unfortunately, the story does not end here as the thiourea group turned out to have unforeseen liabilities of its own that included kidney toxicity and immune suppressive effects.
Abandoning the thiourea group would mean finding an alternative approach to reduce the basicity of the guanidine function. The solution that ultimately led to cimetidine (Tagamet) was to introduce a cyano (nitrile) group on the nitrogen atom of the guanidine group. The electron withdrawing effect of the cyano group lowered the pKa (of the conjugate acid) into a range that allowed for good oral bioavailability while still retaining potency and also avoiding the toxicity observed with metiamide. The H2-receptor antagonists that followed on the success of cimetidine also possess guanidine functions with reduced basicity. Instead of cyano, other electron withdrawing groups such as nitro or sulfonyl are employed to alter the pKa of the guanidine function in drugs such as Zantac and Pepcid. Interestingly, a similar story is being played out in contemporary efforts to find Alzheimer’s therapies that act on the aspartyl protease β-secretase. In these ongoing efforts, the basicity of cyclic guanidine and related inhibitors is being fine-tuned so as to balance potency with other properties such as permeability into the brain and a potentially serious cardiac toxicity. Thus, in seminal drug discovery efforts such as those leading to cimetidine and still today, attention to the acid-base properties of drug leads is central to the development of effective therapies.
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