As my close friends, family and colleagues are probably aware, due to the presence of a gigantic (500ml) bottle of Gaviscon (Figure 1), I have been suffering from a condition known as GERD (Gastroesophageal reflux disease).
Figure 1. Ranitidine (H2 receptor blocker) & Gaviscon (500 ml) prescribed for GERD
Admittedly there are far worse diseases to be afflicted with, however, the symptoms include chronic sore & inflamed throat, heartburn and chest pain which can be rather unpleasant. One of the medications I have been prescribed is ranitidine (a H2 receptor blocker, Figure 1), which is thankfully giving me some relief! The development of ranitidine was in response to the first in class H2 receptor blocker, Cimetidine discovered by Sir James Black at Smith, Kline & French. Sir James Black had an impressive career and is credited for the discovery of both Adrenergic β-blockers & H2 receptor blockers. This was obviously an incredible achievement for which he won the Nobel prize in 1988. How did he do it? more specifically, how did he successfully develop H2 blockers?
After discovering Adrenergic β-blockers Black noted the parallels between the pharmacology of both histamine and adrenaline. By making analogues of histamine one would certainly be able to find histamine β receptor antagonists. The physiological role for histamine was ambiguous at the time however Black observed that patients with peptic ulcers showed increased acid production in response to histamine, in fact it was the basis for diagnosis. Like any drug discovery programme, it wasn’t always straightforward. The medicinal chemists got to work on making antagonists based on the structure of histamine, Black thought making ring analogues of histamine would do the trick as this had worked previously for adrenergic β-blockers. After considerable effort by the chemists, testing in a variety of bioassays, no active compounds were found. It has been stated that the chemists were accused of being ‘’unimaginative’’ (as if that would ever be the case!).
After 4 years of chemical synthesis and no antagonism achieved things were not looking good. Black had a change of heart. Perhaps the chemists should have been spending more time investigating the amino acid side chains than substituting ring structures. Scanning back through earlier data, the sixth compound to be synthesized, Nα-gyanylhistamine, a side chain variant, showed a low level of inhibition and was previously missed because it was only a partial agonist (Table 1). The side chain of Nα-gyanylhistamine was lengthened resulting in 3-[4(5)-imidazolyl]propylguanidine (Table 1) this compound showed an ~6 fold increase in potency but it was still only a partial agonist (Figure 2). Black was eager to find a full antagonist as a partial agonist at a low dose would only stimulate acid production and not block it.
Figure 2. Enhanced potency of the partial agonist 3-[4(5)-imidazolyl]propylguanidine (91488) in guinea-pig right atrium assay.
One significant challenge for the programme was the fact that the compounds synthesized, namely; guanidines, carboxyamidines, isoureas and isothioureas, are all strong bases so at physiological pH would be protonated and therefore not easily absorbed. When the chemists synthesized a set of non-basic compounds both the agonist and antagonist effects were lost, except for one compound, a thiourea analogue (Table 1, PA2= 3.45), which displayed weak, but full, antagonist action in the in vitro guinea pig right atrium assay. Increasing the side chain produced burimamide (Table 1, PA2= 5.11). As had been seen for the guanindine compound this significantly increased the potency, finally they had a selective H2 histamine receptor antagonist. Burimamide took a year to synthesize.
Burimamide was tested in healthy volunteers and shown to inhibit gastric acid secretion confirming the transferability between the animal models and human disease. Burimamide was still not potent enough to be given orally so further compound optimisation was required to develop an even more potent antagonist. Tautomerism and alteration of electronic effects on the imidazole ring bought the chemists to Metiamide (Table 1). Metiamide increased the rate of ulcer healing in 700 patients, however a few suffered from granulocytopenia toxicity. The chemists came to the rescue again, this time replacing the thiourea moiety with cyanoguanidine, and in the process producing the safe drug Cimetidine (Table 1), the first in class H2 receptor blocker.
These drugs have saved the lives of millions of people with heart disease and peptic ulcers. At the time there were few treatment options for patients with peptic ulcers. The only cure was via surgical intervention. Sir James Black and his team are a definite inspiration, just remember his ‘’three C’s for effective drug discovery: Collaboration, Concentration and Commitment’’.
Table 1. Lead optimisation of the first H2 blocker (Source: Personal reflections on Sir James Black (1924-2010) and histamine by C. Robin Ganellin)
Blog written by Jess Booth
To hear James Black in person follow this link: https://www.webofstories.com/play/james.black/12;jsessionid=F3B2C475B86A0B279E9FFEA3119B9C22
Personal reflections on Sir James Black (1924-2010) and histamine by C. Robin Ganellin
Dimaprit-[s-[3-(N, N-dimethylamino)propyl] isothiourea] – a highly specific histamine H2-receptor agonist. Part 2. Structure-activity considerations. Agent Actions. Durant, GJ et al. 1977;7:38-43.
Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists by Alan Wayne Jones
Putting Theory into Practice: James Black, Receptor Theory and the Development of the Beta-Blockers at ICI, 1958–1978 by Viviane Quirke