Metiamide

Metiamide
Metiamide
IUPAC name
N-methyl-N'-(2-{[(4-methyl-1H-imidazol-5-yl)methyl]thio}ethyl)thiourea
Identifiers
PubChem 1548992
ChemSpider 1265996 YesY
DrugBank DB08805
ChEMBL CHEMBL275446 YesY
Jmol-3D images Image 1
Properties
Molecular formula C9H16N4S2
Molar mass 244.38 g mol−1
 YesY (verify) (what is: YesY/N?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Metiamide is a histamine H2-receptor antagonist developed from another H2 antagonist, burimamide.[1] It was an intermediate compound in the development of the successful anti-ulcer drug cimetidine (Tagamet).[2]

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

These changes increased the bioavailability metiamide so that it is 10 times more potent than burimamide in inhibiting histamine-stimulated release of gastric acid.[2] The clinical trials that began in 1973 demonstrated the ability of metiamide to provide symptomatic relief for ulcerous patients by increasing healing rate of peptic ulcers. However, during these trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis (decreased white blood cell count).[2]

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 pKa of the neighbouring nitrogens to the same acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment.

References

  1. ^ Clayden, Jonathan; Greeves, Nick; Warren, Stuart; Wothers, Peter (2001). Organic Chemistry (1st ed.). Oxford University Press. pp. 204–206, 586-588. ISBN 978-0-19-850346-0. 
  2. ^ a b c "Tagamet: A medicine that changed people's lives". American Chemical Society. 2004. http://acswebcontent.acs.org/landmarks/tagamet/tagamet.html. Retrieved 2009-09-06. 


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