Metiamide acts as an antagonist at histamine H1, H2, and H3 receptors, demonstrating varying affinities across these receptor subtypes. Its primary therapeutic target is the histamine H2 receptor (HRH2), which is encoded by the HRH2 gene and plays a central role in regulating gastric acid secretion. At the H2 receptor, metiamide functions as a competitive antagonist, blocking the binding of histamine and thereby preventing the downstream signaling cascade that leads to acid production. The compound exhibits antagonist activity at the H2 receptor with a KB value of 9.2 × 10⁻⁷. In addition to its H2 receptor activity, metiamide also shows antagonist activity at histamine H1 and H3 receptors, with KB values of 0.01 and 0.0000025, respectively. Binding studies have further characterized metiamide's affinity for the histamine H2 receptor in guinea pig tissues. The compound's activity at the H3 receptor (HRH3) has also been documented, with a pKi value of approximately 5.0 in rat models. This multi-receptor profile, while contributing to its pharmacological effects, may also have implications for its toxicity profile.

Metiamide (SK&F 92058) does not compete with the human E3 aldehyde dehydrogenase coenzyme, however it is competitive with aldehyde substrates. Ki has a value of 0.92 μM glycolaldehyde and may bind to both free E3 isoenzymes and enzyme·coenzyme binary complexes as distinct substrates [1]. The data represent percentage changes in GTPase activity driven by methylacetamide as opposed to that produced by HA (100 μM) [2].
Metiamide demonstrates potent inhibition of gastric acid secretion in various in vitro models. In isolated guinea pig atrium and ventricle preparations, metiamide antagonizes histamine-induced chronotropic and inotropic effects in a competitive manner. The compound shows antagonist activity at histamine H2 receptors with an ED50 value of 25 μmol/kg for H2-receptor antagonism. Metiamide also exhibits activity at histamine H1 receptors with a KB of 0.01 and at H3 receptors with a KB of 0.0000025. In functional assays, metiamide inhibits histamine-stimulated acid secretion in isolated gastric mucosa preparations. The compound's effects on acid secretion are dose-dependent, with increasing concentrations leading to greater inhibition. In addition to its effects on acid secretion, metiamide has been shown to influence other physiological parameters, including gastric mucosal blood flow. The compound's activity in vitro provided the foundation for its investigation as a potential therapeutic agent for acid-related disorders, although its development was ultimately halted due to toxicity concerns.

In vivo, metiamide potently inhibits gastric acid secretion across multiple animal species. In dogs, intraarterial injection of metiamide at 2.5 μmol/kg inhibited gastric acid secretion by approximately two-thirds, while intravenous administration at 4.5 μmol/kg produced similar effects. In the Atlantic cod, administration of 10 μmol/kg·h of metiamide completely prevented acid secretion induced by both histamine and carbachol. The compound also demonstrated efficacy in preventing stress ulcers in experimental models of hemorrhagic shock. In cats, metiamide at a dose of 12 µmol/kg·h caused strong inhibition of gastric acid and pepsin secretion and prevented the formation of peptic ulcers induced by histamine and pentagastrin. Compared with the earlier H2 antagonist burimamide, metiamide showed more pronounced effects on gastric secretion and mucosal blood flow. However, comparative studies in dogs revealed that metiamide was slightly less active than cimetidine, while ranitidine was found to be four to nine times more potent than cimetidine depending on the secretagogue used. Despite its efficacy, metiamide's clinical utility was limited by its safety profile, with cases of fatal agranulocytosis reported in patients after several weeks of therapy.

In vitro enzyme/receptor binding assays for metiamide typically employ radioligand displacement techniques using membrane preparations from cells or tissues expressing histamine receptors. For H2 receptor binding, guinea pig gastric mucosal membranes or cells transfected with the human HRH2 gene are commonly used as the source of receptor protein. The assay involves incubating metiamide at varying concentrations with the membrane preparation and a fixed concentration of a radiolabeled H2 receptor antagonist, such as [³H]-tiotidine or [¹²⁵I]-aminopotentidine. Following incubation, bound and free radioligand are separated by rapid filtration through glass fiber filters, and the radioactivity retained on the filters is measured by liquid scintillation counting or gamma counting. Non-specific binding is determined in the presence of a high concentration of an unlabeled H2 receptor antagonist. Binding affinity (Ki) values are calculated from competition curves using nonlinear regression analysis. For H1 and H3 receptor binding, similar methodologies are employed using appropriate radioligands and tissue sources. The PDSP Ki database has curated binding data for metiamide at multiple receptor subtypes.

In vitro cellular assays for metiamide typically utilize cell lines or primary cells that express histamine receptors and respond to histamine stimulation. Gastric parietal cells isolated from animal or human gastric mucosa are commonly employed to assess the compound's ability to inhibit acid secretion. These cells are cultured in appropriate media and stimulated with histamine or other secretagogues in the presence or absence of metiamide. Acid production is measured by assessing the accumulation of [¹⁴C]-aminopyrine, which is taken up by acidic compartments within the parietal cells, or by measuring intracellular pH changes using fluorescent indicators. In addition to parietal cells, cell lines such as CHO cells transfected with H2 receptors or other histamine-responsive cell lines can be used to evaluate receptor antagonism. Functional readouts may include measurement of cAMP accumulation, as H2 receptor activation stimulates adenylyl cyclase activity. Metiamide's effects on cell viability and proliferation can also be assessed using standard cytotoxicity assays such as MTT or resazurin reduction. For studies investigating the compound's toxic effects on bone marrow, colony-forming assays using hematopoietic progenitor cells have been employed to evaluate the impact on stromal and hematopoietic progenitor cells.

In vivo animal experiments for metiamide typically employ rodent or canine models to evaluate the compound's effects on gastric acid secretion and ulcer formation. In rats and mice, metiamide is administered via oral gavage, intraperitoneal injection, or intravenous injection at doses ranging from 5 to 40 mg/kg. Gastric acid secretion is measured in pylorus-ligated animals or in animals with gastric fistulas, with acid output determined by titration of gastric contents. Ulcer models include stress-induced ulcers, histamine-induced ulcers, and bile salt-induced ulcers. In dogs, metiamide is administered intravenously or intraarterially, and gastric acid secretion is measured using gastric fistulas or Heidenhain pouches. In the Atlantic cod, metiamide is administered via infusion, and acid secretion is measured by collection of gastric fluid. For toxicology studies, metiamide is administered to animals over extended periods to assess hematological parameters and bone marrow function. Dosing regimens vary depending on the experimental objectives, with acute studies using single doses and chronic studies using repeated daily administration.

The pharmacokinetic properties of metiamide have been characterized in rats, dogs, and humans through studies using radiolabeled compound. Following administration, metiamide and its metabolites are excreted mainly in the urine irrespective of the route of administration. The compound undergoes metabolism in the liver, and its metabolic oxidation has been studied in the context of species differences and drug pretreatment effects. In human subjects, the metabolism of [¹⁴C]-metiamide has been investigated in individuals phenotyped as extensive or poor metabolizers of debrisoquine, guanoxan, and phenacetin. The absorption of metiamide is adequate for oral bioavailability, and the compound is distributed throughout the body. Metiamide has been shown to affect histamine metabolism in humans, increasing the excretion of 1,4-methylhistamine and decreasing the excretion of histamine in the urine of patients with duodenal ulcer. The compound's pharmacokinetic profile in different species has been examined, with reversible metabolism processes observed in rats. Despite its favorable pharmacokinetic properties for an oral H2 antagonist, metiamide's development was halted due to safety concerns rather than inadequate pharmacokinetic performance.

The toxicity of metiamide is the primary factor that prevented its clinical development and regulatory approval. The most serious adverse effect is agranulocytosis, a life-threatening condition characterized by a severe reduction in circulating neutrophils, which occurred in patients treated with metiamide. A case report documented fatal agranulocytosis in a 55-year-old man with systemic mastocytosis after seven weeks of metiamide therapy. The toxicity is attributed to the thiourea fragment present in the molecule, which undergoes bioactivation to reactive metabolites that damage bone marrow cells. In vitro studies using colony-forming assays for bone-marrow stromal and hematopoietic progenitor cells have demonstrated that metiamide causes direct toxicity to these cells. It has been suggested that bone-marrow stromal cell damage may be an important contributory factor in the hematopoietic toxicity of metiamide. Nephrotoxicity has also been reported as a concern with metiamide use. These toxic effects were sufficiently severe that the compound was abandoned in favor of cimetidine, which, through structural modification replacing the thiourea group with a cyanoguanidine moiety, retained H2 antagonist activity while exhibiting a more acceptable safety profile.

[1]. Alexandra Kikonyogo ,Regina Pietruszko, Cimetidine and Other H2-Receptor Antagonists as Inhibitors of Human E3 Aldehyde Dehydrogenase. Molecular Pharmacology 1997; 52: 2267-271.

[2]. Hendrik Preuss, Prasanta Ghorai1, Anja Kraus, Constitutive Activity and Ligand Selectivity of Human, Guinea Pig, Rat, and Canine Histamine H2 Receptors. JPET 2007 vol. 321no. 3 983-995.

Metiamide belongs to the imidazole class of compounds. Metiamide is an H2 receptor antagonist derived from bremine. It is an intermediate in the development of cimetidine. Metiamide is a histamine H2 receptor antagonist used as an anti-ulcer drug. Drug Indications It can be used to treat and control gastroesophageal reflux disease (GERD), peptic ulcers, heartburn, and acid dyspepsia. Mechanism of Action Metiamide binds to H2 receptors located on the basolateral membrane of gastric parietal cells, blocking the action of histamine. This competitive inhibition leads to reduced gastric acid secretion, decreased gastric volume, and decreased acidity. Pharmacodynamics Metiamide is a histamine H2 receptor antagonist. It reduces basal and nocturnal gastric acid secretion and decreases gastric volume, gastric acidity, and the amount of gastric acid secreted in response to stimuli such as food, caffeine, insulin, betahistazole, or pentagastrin. Metiamide inhibits multiple isoenzymes of the hepatic CYP450 enzyme system. Other effects of methimazole include increasing the gut microbiota, such as nitrate-reducing bacteria.
Metiamide was developed by Smith Kline & French Laboratories as part of a systematic medicinal chemistry program aimed at discovering histamine H2 receptor antagonists for the treatment of peptic ulcer disease. The compound was an intermediate in the development pathway from burimamide, the first H2 antagonist, to cimetidine, which became a blockbuster drug. Metiamide demonstrated promising clinical efficacy in patients with duodenal ulcers, potently inhibiting gastric acid secretion. However, its development was halted due to the occurrence of agranulocytosis and nephrotoxicity. The toxicity was attributed to the thiourea moiety, which undergoes bioactivation to reactive intermediates. This finding guided further optimization efforts that led to the replacement of the thiourea group with a cyanoguanidine group in cimetidine, which retained H2 antagonist activity while eliminating the toxicity. Metiamide thus represents a critical case study in drug development, demonstrating the importance of identifying and eliminating toxicophores early in the drug discovery process. It is no longer used clinically and is primarily of historical interest in the context of medicinal chemistry and the development of acid-suppressive therapy.

C9H16N4S2

244.375

244.081

34839-70-8

1548992

White to off-white solid powder

1.2±0.1 g/cm3

463.0±55.0 °C at 760 mmHg

233.8±31.5 °C

0.0±1.1 mmHg at 25°C

1.627

0.65

3

3

5

15

201

0

FPBPLBWLMYGIQR-UHFFFAOYSA-N

InChI=1S/C9H16N4S2/c1-7-8(13-6-12-7)5-15-4-3-11-9(14)10-2/h6H,3-5H2,1-2H3,(H,12,13)(H2,10,11,14)

1-methyl-3-[2-[(5-methyl-1H-imidazol-4-yl)methylsulfanyl]ethyl]thiourea

SKF-92058 SKF92058 NSC-307755 SKF 92058 SK&F 92058 NSC 307755

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~2.4 mg/mL (~9.82 mM)
H2O : ~1.67 mg/mL (~6.83 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)