Metiamide is a histamine H₂ receptor antagonist developed from another H₂ antagonist, burimamide. 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 burimamide is largely inactive at physiological pH, due to the presence of its

electron The electron ( or ) is a subatomic particle with a negative one elementary electric charge. Electrons belong to the first generation of the lepton particle family, and are generally thought to be elementary particles because they have no kn ...

-donating

side chain In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called the "main chain" or backbone. The side chain is a hydrocarbon branching element of a molecule that is attached to a l ...

, 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 Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole Diazole refers ...

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

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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

metiamide so that it is ten times more potent than burimamide 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 Peptic ulcer disease (PUD) is a break in the inner lining of the stomach, the first part of the small intestine, or sometimes the lower esophagus. An ulcer in the stomach is called a gastric ulcer, while one in the first part of the intestines i ...

. 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 Thiourea () is an organosulfur compound with the formula and the structure . It is structurally similar to urea (), except that the oxygen atom is replaced by a sulfur atom (as implied by the ''thio-'' prefix); however, the properties of urea ...

group was the cause of the

. Therefore, replacement of the

thiocarbonyl In organic chemistry, thioketones (; also known as thiones or thiocarbonyls) are organosulfur compounds related to conventional ketones in which the oxygen has been replaced by a sulfur. Instead of a structure of , thioketones have the structu ...

in the

group was suggested: * with

urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...

guanidine Guanidine is the compound with the formula HNC(NH2)2. It is a colourless solid that dissolves in polar solvents. It is a strong base that is used in the production of plastics and explosives. It is found in urine predominantly in patients experie ...

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 ...

nitro group In organic chemistry, nitro compounds are organic compounds that contain one or more nitro functional groups (). The nitro group is one of the most common explosophores (functional group that makes a compound explosive) used globally. The nitr ...

prevented the guanidine group from being protonated and did not cause

The nitro and cyano groups are sufficiently

electronegative Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the d ...

to reduce the pK_a of the neighboring

nitrogen Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...

s to the same

acidity In computer science, ACID ( atomicity, consistency, isolation, durability) is a set of properties of database transactions intended to guarantee data validity despite errors, power failures, and other mishaps. In the context of databases, a sequ ...

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 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 The Birch reduction is an organic reaction that is used to convert arenes to cyclohexadienes. The reaction is named after the Australian chemist Arthur Birch and involves the organic reduction of aromatic rings in an amine solvent (traditionally ...

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 In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...

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 Methyl isothiocyanate is the organosulfur compound with the formula CH3N=C=S. This low melting colorless solid is a powerful lachrymator. As a precursor to a variety of valuable bioactive compounds, it is the most important organic isothiocyanat ...

gives metiamide (6). Metiamide synthesis

References

{{Histaminergics H2 receptor antagonists Imidazoles Thioethers Thioureas