657-24-9 Usage
Description
The study of metformin and its hypoglycemic effects originated from the study of
goat’s rue plants, also known as Galega officinalis(French lilac). Goat’s
rues are native plants in the Middle East and introduced to Europe later and have
been used as forage and ornamental plants throughout the world, including China.
As early as in the Middle Ages in Europe, it was found that goat’s rues could ease
polyuria, which is one of the typical symptoms of diabetes. While goat’s rues were
used to treat a variety of other diseases in the Middle Ages, it was found to cause
poisoning symptoms in livestock. Goat’s rues are still used as medical plants at
present, mainly for diabetes, diuretic, hepatoprotection, aiding in digestion and promoting lactation, etc. In China, goat’s rues were recorded first in the dictionary of
Chinese seed plants and mainly used for the treatment of diabetes. However, because
of high toxicity, it is rarely used in traditional Chinese medicines at present.
Physical properties
Appearance: white crystalline or crystalline powder, odorless. Solubility: freely
soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in
chloroform or ether. Melting point: 223–226°C.
History
Metformin is a biguanide compound which originated from the extraction of goat’s
rue plants. The structure of metformin was identified by British scholars in the early
1920s. In 1922, Werner and Bell et?al. first synthesized metformin in 31 institutes in
Dublin, Ireland. In 1929, Slotta and Tschesche found metformin’s hypoglycemic action. However, because of other potent antidiabetic drugs such as insulin
which were widely used in clinical practice, the pharmacological effects of metformin didn’t receive much attention.Until the 1950s, a French diabetic scientist Jean Sterne found the hypoglycemic
effect of metformin through the study of galegine. Then the drug was used in diabetic patients for the first time, and the results were published in 1957. UKPDS, which began from 1977 and ended in 1997 and
was then followed up for 10?years, is the longest in the history of clinical trials and
has a significant impact on practice and guidelines for prevention and treatment of
diabetes mellitus. In this trial, metformin was found to reduce the risk of diabetic
complications by 32%. In addition, it was proved for the first time that metformin
can reduce blood glucose and protect against cardiovascular function, especially in
obese patients. In 1994, metformin was approved by the US FDA for type 2
diabetes treatment. Currently, metformin has become the world’s most widely used
antidiabetic drug.Aiming at improving the stability of the absorption of metformin, chemists have
also carried out a series of structural renovation and modification. Metformin activates with carbonyl, esters, chlorides, and aldehydes to form triazine compounds,
with 1,3-diketone to produce pyrimidine compounds, and with disulfides to produce
C-S coupling products, etc.
Uses
non-insulin dependent diabetes mellitus
Indications
Metformin
(Glucophage) was used in Europe for many years before
it was approved for use in the United States in
1995. Metformin is the only approved biguanide for the
treatment of patients with NIDDM that are refractory
to dietary management alone. Metformin does not affect
insulin secretion but requires the presence of insulin
to be effective. The exact mechanism of metformin’s
action is not clear, but it does decrease hepatic
glucose production and increase peripheral glucose uptake.
When used as monotherapy, metformin rarely
causes hypoglycemia.
Definition
ChEBI: Metformin is a member of the class of guanidines that is biguanide the carrying two methyl substituents at position 1. It has a role as a hypoglycemic agent, a xenobiotic, an environmental contaminant and a geroprotector. It is functionally related to a biguanide. It is a conjugate base of a metformin(1+).
Therapeutic Function
Oral hypoglycemic
Biological Functions
Metformin can lower free fatty acid concentrations by 10 to 30%.
This antilipolytic effect may help to explain the reduction in gluconeogenesis through reduced levels of available substrate
(65). When given as a monotherapy, metformin treatment does not lead to hypoglycemia, so it is better described as an
antihyperglycemic agent rather than a hypoglycemic agent.
General Description
Metformin, N,N-dimethylimidodicarbonimidicdiamide hydrochloride (Glucophage), is a bisguanidine.This class of agents is capable of reducing sugar absorptionfrom the gastrointestinal tract. Also, they can decrease gluconeogenesiswhile increasing glucose uptake by muscles andfat cells. These effects, in turn, lead to lower blood glucoselevels. Unlike the sulfonylureas, these are not hypoglycemicagents but rather can act as antihyperglycemics. This differencein nomenclature is caused by the inability of these agentsto stimulate the release of insulin from the pancreas. Often,metformin is coadministered with the nonsulfonylureas to improvethe efficacy of those agents.
Pharmacology
As a traditional antidiabetic drug, metformin can reduce the levels of blood glucose and lipid, as well as regulating cell growth, anti-inflammation, antiaging, etc. The main pharmacological mechanisms are inhibition of hepatic gluconeogenesis, the activation of AMP-activated protein kinase (AMPK), and the regulation of mitochondrial function.
Improvement of Insulin Resistance and Decrease of Blood Glucose Levels
The main pharmacological effects of biguanide drugs are to reduce blood glucose output and improve peripheral insulin resistance. Metformin inhibits hyperglycemia mainly by inhibiting hepatic glucose production (hepatic gluconeogenesis), increasing muscle glucose uptake.
Regulation of Lipid Metabolism and Reducing Body Weight
Metformin can reduce the blood triglycerides in circulation, improve liver steatosis, promote the oxidation of brown adipose tissue and VLDL-fatty acid triglyceride uptake, and inhibit fat formation; the process may be related with the activation of AMPK. AMPK can phosphorylate acetyl coenzyme A carboxylase (ACC) and inhibit the conversion of acetyl coenzyme A into malonyl-CoA. Malonyl-CoA is a precursor of fatty acid production and is an allosteric inhibitor of fatty acid transporting to mitochondria.
Prevention and Treatment of Tumors
Epidemiological studies have shown that metformin reduced the risk of multiple types of tumors in type 2 diabetes and nondiabetes patients and reduced tumor-related mortality. Metformin also has a therapeutic effect on various tumors. The antitumor effect of metformin may be through the reduction of serum insulin and insulin-like growth factor-1 (IGF-1) levels or activation of LKB1/AMPK, thereby blocking the mammalian target of rapamycin-sensitive complex 1 (mTORC1) signaling pathway.
Antiaging Antiaging effect is a major discovery in the new role of metformin. FDA approved the phase 4 of clinical trial of metformin for antiaging effect, and the trial is ongoing. The study suggests that the antiaging effect of metformin is closely related to the mitochondria, through the regulation of mitochondrial function to activate AMPK and inhibit mTOR, thereby reducing energy consumption. Furthermore, metformin can regulate oxidative stress, reduce tissue inflammation, and reduce the growth factor level and cell proliferation. The above effects and the combinational effect result in the improvement of health and achieving longevity.
Other Effects Studies have shown that metformin helps to prevent type 2 diabetes. For young people with a high body mass index, metformin is more effective than lifestyle control. In addition, metformin can improve and prevent vascular disease, improve mitochondrial function, and serve as anti-inflammatory agent and antioxidant.
Metformin is hydrophilic and distributed in tissues in an active manner. After
oral administration, metformin is absorbed quickly and rapidly distributed into various tissues, mainly in the liver, gastrointestinal tract, and kidney.
Clinical Use
Metformin works best in patients with significant
hyperglycemia and is often considered first-line therapy
in the treatment of mild to moderate type II overweight
diabetics who demonstrate insulin resistance. The
United Kingdom Prospective Diabetes Study demonstrated
a marked reduction in cardiovascular comorbidities
and diabetic complications in metformintreated
individuals. Metformin has also been used to
treat hirsutism in individuals with polycystic ovarian
syndrome and may enhance fertility in these women,
perhaps by decreasing androgen levels and enhancing
insulin sensitivity.
Safety Profile
Poison by
subcutaneous and intraperitoneal routes.
Mildly toxic by parenteral route.
Experimental teratogenic effects. Mutation
data reported. When heated to
decomposition it emits toxic fumes of NOx
Metabolism
Metformin is quickly absorbed from the small intestine. Bioavailability is from 50 to 60%, and the drug is not protein bound.
Peak plasma concentrations occur at approximately 2 hours. The drug is widely distributed in the body and accumulates in the wall of the small intestine. This depot of drug serves to maintain plasma concentrations. Metformin is excreted in the
urine, via tubular excretion, as unmetabolized drug with a half-life of approximately 2 to 5 hours; therefore, renal impairment
as well as hepatic disease are contraindications for the drug.
Check Digit Verification of cas no
The CAS Registry Mumber 657-24-9 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 6,5 and 7 respectively; the second part has 2 digits, 2 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 657-24:
(5*6)+(4*5)+(3*7)+(2*2)+(1*4)=79
79 % 10 = 9
So 657-24-9 is a valid CAS Registry Number.
InChI:InChI=1/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8)
657-24-9Relevant articles and documents
A ternary tetracoordinated PdII complex with metformin and dipicolinate: Synthesis, characterization and crystal structure
Moghimi,Khavassi,Dashtestani,Kordestani,Ekram Jafari,Maddah,Moosavi
, p. 38 - 41 (2011)
A proton transfer compound L, (MetH)2(dipic), (dipicH 2 = 2,6-pyridinedicarboxylic acid and Met = Metformin (N,N-dimethylebiguanidine), was synthesized and characterized by IR, 1H and 13C NMR spectroscopy. The reaction of L with PdCl2 in water results in the formation of novel tetracoordinated PdII complex [Pd(dipic)(Met)]·2H2O indicating the participation of both dipic2- and Met as chelating ligands. This complex was characterized by single crystal X-ray analysis. The crystal system is monoclinic with space group P21/c. The unit cell dimensions for PdII complex 1 is a = 8.8619(14) , b = 9.5072(9) , c = 19.153(3) .
Convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of metformin
Huttunen, Kristiina M.,Lepp?nen, Jukka,Laine, Krista,Veps?l?inen, Jouko,Rautio, Jarkko
, p. 624 - 628 (2013)
A convenient microwave-assisted synthesis of lipophilic sulfenamide prodrugs of antidiabetic agent, metformin, is reported in this study. These acyclic prodrugs were synthesized directly from selected disulfides with basic metformin and silver nitrate by a one-pot reaction under microwave irradiation. The prepared prodrugs had significantly increased lipophilicity, which resulted in excellent permeability of the octylthio prodrug of metformin across a Caco-2 cell monolayer. According to our preliminary in vivo studies, the octylthio prodrug was also absorbed mostly intact after oral administration in rats. In conclusion, this study shows that these types of more lipophilic sulfenamide prodrugs can be promising candidates to improve permeability and passive absorption of highly water-soluble metformin.
Two N,N-dimethylbiguanidium salts displaying double hydrogen bonds to the counter-ions
Lu, Li-Ping,Zhang, Hong-Mei,Feng, Si-Si,Zhu, Miao-Li
, (2004)
An investigation into the crystal structures of N,N-dimethylbiguanidium salts was made. Compound (I) in N,N-dimethylbiguanidium contained one N,N dimethylbiguanidium dictation, one oxalate anion and one water molecule. Compound (II) consisted of one N,N-d
Sulfonamide metformin derivatives induce mitochondrial-associated apoptosis and cell cycle arrest in breast cancer cells
Huttunen, Johanna,Huttunen, Kristiina M.,Markowicz-Piasecka, Magdalena,Sikora, Joanna,Zajda, Agnieszka
, (2021/12/31)
Metformin, an oral anti-diabetic drug, has attracted scientific attention due to its anti-cancer effects. This biguanide exerts preventive effects against cancer, and interferes with cancer-promoting signaling pathways at the cellular level. However, the direct cytotoxic or anti-proliferative effect of the drug is observed at very high concentrations, often exceeding 5–10 mM. This paper presents the synthesis of eight novel sulfonamide-based biguanides with improved cellular uptake in two breast cancer cell lines (MCF-7 and MDA-MB-231), and evaluates their effects on cancer cell growth. The synthesized sulfonamide-based analogues of metformin (1–5) were efficiently taken up in MCF-7 and MDA-MB-231 cells, and were characterized by stronger cytotoxic properties than those of metformin. Generally, compounds were more effective in MCF-7 than in MDA-MB-231. Compound 2, with an n-octyl chain, was the most active molecule with IC50 = 114.0 μmol/L in MCF-7 cells. The cytotoxicity of compound 2 partially results from its ability to induce early and late apoptosis. Increased intracellular reactive oxygen species (ROS) production and reduced mitochondrial membrane potential suggest that compound 2 promotes mitochondrial dysfunction and activates the mitochondrial-associated apoptosis-signaling pathway. In addition, compound 2 was also found to arrest cell cycle in the G0/G1 and G2/M phase and significantly inhibit cancer cell migration. In conclusion, this study supports the hypothesis that improved transporter-mediated cellular uptake of potential drug molecule is accompanied by its increased cytotoxicity. Therefore, compound 2 is a very good example of how chemical modification of a biguanide scaffold can affect its biological properties and improve anti-neoplastic potential.