Metiamide is a histamine H
2-receptor antagonist developed from another H
2 antagonist,
burimamideBurimamide is an antagonist at the H
2 and H
3 histamine receptors. It is largely inactive as an H
2 antagonist at physiological pH, but its H
3 affinity is 100x higher...
. It was an intermediate compound in the development of the successful anti-ulcer drug
cimetidineCimetidine is a histamine H
2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers...
(Tagamet).
Development of metiamide from burimamide
After discovering that
burimamideBurimamide is an antagonist at the H
2 and H
3 histamine receptors. It is largely inactive as an H
2 antagonist at physiological pH, but its H
3 affinity is 100x higher...
is largely inactive at physiological pH, due to the presence of its
electronAn electron is a subatomic particle that carries a negative electric charge. It has no known substructure and is believed to be a point particle. An electron has a mass that is approximately 1836 times less than that of the proton. The intrinsic angular momentum of the electron is a half integer...
donating side chain, the following steps were undertaken to stabilse burimamide:
- addition of a sulfide
A thioether is a functional group in organic chemistry that has the structure R1-S-R2 as shown on right. Like many other sulfur-containing compounds, volatile thioethers characteristically have foul odors....
group close to the imidazoleImidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents...
ring, giving thiaburimamide
- addition of methyl group to the 4- position on the imidazole
Imidazole is an organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid. Imidazole refers to the parent compound whereas imidazoles are a class of heterocycles with similar ring structure but varying substituents...
ring to favour the tautomerTautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. It is common that this reaction results in the formal migration of a hydrogen atom or proton, accompanied by a switch of a single bond and adjacent double bond. In solutions in which...
of thiaburimamide which binds better to the H2-receptor
These changes increased the
bioavailabilityIn pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%...
metiamide so that it is 10 times more potent than
burimamideBurimamide is an antagonist at the H
2 and H
3 histamine receptors. It is largely inactive as an H
2 antagonist at physiological pH, but its H
3 affinity is 100x higher...
in inhibiting histamine-stimulated release of
gastric acidGastric acid is a secretion produced in the stomach. It is one of the main ditotonic solutions secreted, together with several enzymes and intrinsic factors...
. 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
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
(decreased white blood cell count).
Modification of metiamide to cimetidine
It was determined that the
thioureaThiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the formula CSN
2H
4 or
2CS. It is similar to urea, except that the oxygen atom is replaced by a sulfur atom. The properties of urea and thiourea differ significantly because of the...
group was the cause of the
agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
. Therefore replacement of the
=SThe thionyl group is SO, a sulfur atom plus an oxygen atom.It occurs in compounds such as thionyl fluoride, SOF2.Thionyl chloride, SOCl2, is a common reagent used in organic synthesis to convert carboxylic acids to acyl chlorides....
in the
thioureaThiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the formula CSN
2H
4 or
2CS. It is similar to urea, except that the oxygen atom is replaced by a sulfur atom. The properties of urea and thiourea differ significantly because of the...
group was suggested:
- with =O
Urea or carbamide is an organic compound with the chemical formula
2CO. The molecule has two amine residues joined by a carbonyl functional group....
or =NHGuanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...
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 agonist
An agonist is a drug that binds to a receptor of a cell and triggers a response by the cell. An agonist often mimics the action of a naturally occurring substance.An agonist produces an action...
ic effects
- to prevent the guanidine
Guanidine is a crystalline compound of strong alkalinity formed by the oxidation of guanine. It is used in the manufacture of plastics and explosives. It is found in urine as a normal product of protein metabolism. The molecule was first synthesized in 1861 by the oxidative degradation of an...
group being protonated at physiological pH, electron-withdrawing groups were added
- adding a -C≡N
A nitrile is any organic compound which has a -C≡N functional group. The -C≡N functional group is called a nitrile group. In the -CN group, the carbon atom and the nitrogen atom are triple bonded together. The prefix cyano is used in chemical nomenclature to indicate the presence of a nitrile...
or -NO2Nitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group. The presence of impurities or improper handling can trigger a violent exothermic decomposition...
group prevented the guanidine group being protonated and did not cause agranulocytosisAgranulocytosis, also known as agranulosis, is an acute condition involving a severe and dangerous leukopenia, most commonly of neutrophils, causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...
The
nitroNitro compounds are organic compounds that contain one or more nitro functional groups . They are often highly explosive, especially when the compound contains more than one nitro group. The presence of impurities or improper handling can trigger a violent exothermic decomposition...
and cyano groups are sufficiently electronegative to reduce the pK
a of the neighbouring
nitrogenNitrogen is a chemical element that has the symbol N and atomic number 7 and atomic mass 14.00674 u. Elemental nitrogen is a colorless, odorless, tasteless and mostly inert diatomic gas at standard conditions, constituting 78% by volume of Earth's atmosphere.Many industrially important...
s to the same acidity of the
thioureaThiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the formula CSN
2H
4 or
2CS. It is similar to urea, except that the oxygen atom is replaced by a sulfur atom. The properties of urea and thiourea differ significantly because of the...
group, hence preserving the activity of the drug in a physiological environment.