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Metiamide
 
 
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Metiamide is an H2-receptor antagonist
H2-receptor antagonist

The H2-receptor antagonists are a class of medication used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells....
 developed from another H2 antagonist, burimamide
Burimamide

Burimamide is an Receptor antagonist at the Histamine H2 receptor and Histamine H3 receptor histamine Receptor . It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher....
.

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

Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers....
 (Tagamet).

r discovering that burimamide
Burimamide

Burimamide is an Receptor antagonist at the Histamine H2 receptor and Histamine H3 receptor histamine Receptor . It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher....
 is largely inactive at physiological pH, due to the presence of its electron
Electron

The electron is a subatomic particle that carries a negative electric charge. It has elementary particle and is believed to be a point particle....
 donating side chain
Side chain

A side chain in organic chemistry and biochemistry is a part of a molecule that is attached to a core structure. The placeholder R is often used as a generic placeholder for side chains, the R historically being derived from radical or rest....
, the following steps were undertaken to stabilse burimamide:



Metiamide

However,

as determined that the thiourea
Thiourea

Thiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the chemical formula CarbonSulfurNitrogen2Hydrogen4 or 2CarbonSulfur....
 group was the cause of the agranulocytosis
Agranulocytosis

Agranulocytosis is an acute condition involving a severe and dangerous leukopenia particularly of neutrophils causing a neutropenia in the circulating blood....
.






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Metiamide is an H2-receptor antagonist
H2-receptor antagonist

The H2-receptor antagonists are a class of medication used to block the action of histamine on parietal cells in the stomach, decreasing the production of acid by these cells....
 developed from another H2 antagonist, burimamide
Burimamide

Burimamide is an Receptor antagonist at the Histamine H2 receptor and Histamine H3 receptor histamine Receptor . It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher....
.

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

Cimetidine is a histamine H2-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 burimamide
Burimamide

Burimamide is an Receptor antagonist at the Histamine H2 receptor and Histamine H3 receptor histamine Receptor . It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher....
 is largely inactive at physiological pH, due to the presence of its electron
Electron

The electron is a subatomic particle that carries a negative electric charge. It has elementary particle and is believed to be a point particle....
 donating side chain
Side chain

A side chain in organic chemistry and biochemistry is a part of a molecule that is attached to a core structure. The placeholder R is often used as a generic placeholder for side chains, the R historically being derived from radical or rest....
, the following steps were undertaken to stabilse burimamide:

  • addition of a sulfide
    Thioether

    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 organic compound thioethers characteristically have foul odors....
     group close to the imidazole
    Imidazole

    Imidazole is a organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid....
     ring, giving thiaburimamide
  • addition of methyl group to the 4- position on the imidazole
    Imidazole

    Imidazole is a organic compound with the formula C3H4N2. This aromatic heterocyclic is classified as an alkaloid....
     ring to favour the tautomer
    Tautomer

    Tautomers are isomers of organic compounds that readily interconvert by a chemical reaction called tautomerization. Commonly 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....
     of thiaburimamide which binds better to the H2-receptor


Metiamide
  • is 10 times more potent than burimamide
    Burimamide

    Burimamide is an Receptor antagonist at the Histamine H2 receptor and Histamine H3 receptor histamine Receptor . It is largely inactive as an H2 antagonist at physiological pH, but its H3 affinity is 100x higher....
  • inhibited histamine-stimulated release of gastric acid
    Gastric acid

    Gastric acid is one of the main secretions of the stomach, together with several enzymes and intrinsic factor. Chemically it is an acid solution with a pH of 1 to 2 in the stomach lumen , consisting mainly of hydrochloric acid , and large quantities of potassium chloride and sodium chloride ....
  • increased healing rate of peptic ulcers
  • provided symptomatic relief for ulcerous patients.


However,
  • in clinical trials, an unacceptable number of patients dosed with metiamide developed agranulocytosis
    Agranulocytosis

    Agranulocytosis is an acute condition involving a severe and dangerous leukopenia particularly of neutrophils causing a neutropenia in the circulating blood....
     (decreased white blood cell count)
  • clinical trials aborted, as patients were left susceptible to infection


Modification of metiamide to cimetidine

It was determined that the thiourea
Thiourea

Thiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the chemical formula CarbonSulfurNitrogen2Hydrogen4 or 2CarbonSulfur....
 group was the cause of the agranulocytosis
Agranulocytosis

Agranulocytosis is an acute condition involving a severe and dangerous leukopenia particularly of neutrophils causing a neutropenia in the circulating blood....
. Therefore replacement of the =S
Thionyl

The 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 thiourea
Thiourea

Thiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the chemical formula CarbonSulfurNitrogen2Hydrogen4 or 2CarbonSulfur....
 group was suggested:

  • with =O
    Urea

    Urea is an organic compound with the chemical formula 2carbonoxygen.Urea is also known by the International Nonproprietary Name carbamide, as established by the World Health Organization....
     or =NH
    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....
     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
    Agonist

    An agonist is a term used to describe a type of Ligand or drug that binds and alters the activity of a Receptor . The ability to alter the activity of a receptor, also known as the agonist's efficacy is a property that distinguishes it from receptor antagonist, a type of receptor ligand which also binds a receptor but which does not alter t...
    ic effects
  • to prevent the guanidine
    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....
     group being protonated at physiological pH, electron-withdrawing groups were added
  • adding a -C=N
    Nitrile

    A nitrile is any organic compound which has a -Carbon=Nitrogen functional group. The -C=N functional group is called a nitrile group....
     or -NO2
    Nitro compound

    Nitro 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....
     group prevented the guanidine group being protonated and did not cause agranulocytosis
    Agranulocytosis

    Agranulocytosis is an acute condition involving a severe and dangerous leukopenia particularly of neutrophils causing a neutropenia in the circulating blood....


The nitro
Nitro compound

Nitro 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....
 and cyano groups are sufficiently electronegative to reduce the pKa of the neighbouring nitrogen
Nitrogen

Nitrogen is a chemical element that has the symbol N and atomic number 7 and atomic mass 14.00674?. Elemental nitrogen is a colorless, odorless, tasteless and mostly inert diatomic gas at standard conditions, constituting 78% by volume of Earth's atmosphere....
s to the same acidity of the thiourea
Thiourea

Thiourea is an organic compound of carbon, nitrogen, sulfur and hydrogen, with the chemical formula CarbonSulfurNitrogen2Hydrogen4 or 2CarbonSulfur....
 group, hence preserving the activity of the drug in a physiological environment.

  • the -C=N group (part of a cyanoguanidine moiety
    Moiety

    Moiety may mean:*A part or half of a molecule *In anthropology, a type of descent group*An Australian Aboriginal kinship*Native Hawaiian realm ruled by a Mo'i or Ali'i...
    ) was a little more effective
  • it was developed and marketed as cimetidine
    Cimetidine

    Cimetidine is a histamine H2-receptor antagonist that inhibits the production of acid in the stomach. It is largely used in the treatment of heartburn and peptic ulcers....
    ,