Metiamide is a histamine H₂ receptor antagonist developed from another H₂ antagonist,

burimamide Burimamide is an antagonist at the H2 and H3 histamine receptors. It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher. It is a thiourea derivative. Burimamide was first developed by scientists at S ...

. It was an intermediate compound in the development of the successful anti-ulcer drug

cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...

(Tagamet).

Development of metiamide from burimamide

After discovering that

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 Sulfide (British English also sulphide) is an inorganic anion of sulfur with the chemical formula S2− or a compound containing one or more S2− ions. Solutions of sulfide salts are corrosive. ''Sulfide'' also refers to chemical compounds lar ...

group close to the imidazole ring, giving thiaburimamide * addition of

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

group to the 4-position on the imidazole ring to favor the

tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...

of thiaburimamide which binds better to the H₂ receptor These changes increased the bioavailability metiamide so that it is ten times more potent than

in inhibiting histamine-stimulated release of

gastric acid Gastric acid, gastric juice, or stomach acid is a digestive fluid formed within the stomach lining. With a pH between 1 and 3, gastric acid plays a key role in digestion of proteins by activating digestive enzymes, which together break down the ...

. 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 Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...

(decreased white blood cell count).

Modification of metiamide to cimetidine

It was determined that the thiourea group was the cause of the

. Therefore, replacement of the thiocarbonyl in the thiourea group was suggested: * with urea or guanidine resulted in a compound with much less activity (only 5% of the potency of metiamide) * however, the NH form (the guanidine analog of metiamide) did not show

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

ic effects * to prevent the guanidine group being protonated at physiological pH, electron-withdrawing groups were added * adding a

nitrile In organic chemistry, a nitrile is any organic compound that has a functional group. The prefix ''cyano-'' is used interchangeably with the term ''nitrile'' in industrial literature. Nitriles are found in many useful compounds, including met ...

or nitro group prevented the guanidine group from being protonated and did not cause

The nitro and cyano groups are sufficiently electronegative to reduce the pK_a 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 equivalent An equivalent (symbol: officially equiv; unofficially but often Eq) is the amount of a substance that reacts with (or is ''equivalent'' to) an arbitrary amount (typically one mole) of another substance in a given chemical reaction. It is an arch ...

s of

formamide Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticide ...

(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 Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermediate pantetheine is broken down into cysteamine and pantothenic acid. It is the biosynthetic precursor to ...

(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 In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are ...

without competition and the acid also activates the alcoholic function toward displacement. Finally, condensation of the amine with methyl isothiocyanate gives metiamide (6). Metiamide synthesis

References

{{Histaminergics H2 receptor antagonists Imidazoles Thioethers Thioureas