Metiamide

Metiamide is an H₂-receptor antagonist developed from another H₂ antagonist, burimamide.

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It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine (Tagamet®).

Development of metiamide from burimamide

After discovering that burimamide is largely inactive at physiological pH, due to the presence of its electron donating side chain, the following steps were undertaken to stabilse burimamide:

• addition of a sulfide group close to the imidazole ring, giving thiaburimamide
• addition of methyl group to the 4- position on the imidazole ring to favour the tautomer of thiaburimamide which binds better to the H₂-receptor

Metiamide

• is 10 times more potent than burimamide
• inhibited histamine-stimulated release of gastric acid
• increased healing rate of peptic ulcers
• provided symptomatic relief for ulcerous patients.

However,

• in clinical trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis (decreased white blood cell count)
• clinical trials aborted, as patients were left susceptible to infection

Modification of metiamide to cimetidine

It was determined that the thiourea group was the cause of the agranulocytosis. Therefore replacement of the =S in the thiourea group was suggested:

• with =O or =NH resulted in a compound with much less activity (20 times less than metiamide)
• however, the NH form (the guanidine analogue of metiamide) did not show agonistic effects
• to prevent the guanidine group being protonated at physiological pH, electron-withdrawing groups were added
• adding a -C≡N or -NO₂ group prevented the guanidine group being protonated and did not cause agranulocytosis

The nitro and cyano groups are sufficiently electronegative to reduce the pK_a of the neighbouring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment.

• the -C≡N group (part of a cyanoguanidine moiety) was a little more effective
• it was developed and marketed as cimetidine,

References

• Clayden, J. Greeves, N. Warren, S. Wothers, P. (2001). Organic Chemistry. Oxford. ISBN 0-19-850346-6