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 stabilize 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 favor the
tautomer of thiaburimamide which binds better to the H2 receptor
These changes increased the
bioavailability metiamide so that it is ten 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]
The nitro and cyano groups are sufficiently
electronegative to reduce the
pKa of the neighboring
nitrogens to the same
acidity of the thiourea group, hence preserving the activity of the drug in a physiological environment.
Synthesis
Reacting ethyl 2-chloroacetoacetate (1) with 2
molar equivalents of
formamide (2) gives 4-carboethoxy-5-methylimidazole (3). Reduction of the carboxylic ester (3) with sodium in liquid ammonia via
Birch reduction gives the corresponding alcohol (4). Reaction of that with
cysteamine (mercaptoethylamine), as its hydrochloride, leads to intermediate 5. In the strongly acid medium, the amine is completely protonated; this allows the
thiol to express its
nucleophilicity without competition and the acid also activates the alcoholic function toward displacement. Finally, condensation of the amine with
methyl isothiocyanate gives metiamide (6).
^Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Roe, A. M.; Slater, R. A. (1976). "Potential histamine H2-receptor antagonists. 3. Methylhistamines". Journal of Medicinal Chemistry. 19 (7): 923–928.
doi:
10.1021/jm00229a013.
PMID7675.
^Durant, G. J.; Emmett, J. C.; Ganellin, C. R.; Miles, P. D.; Parsons, M. E.; Prain, H. D.; White, G. R. (1977). "Cyanoguanidine-thiourea equivalence in the development of the histamine H2-receptor antagonist, cimetidine". Journal of Medicinal Chemistry. 20 (7): 901–906.
doi:
10.1021/jm00217a007.
PMID17751.