1,1-Dimethylbiguanide
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Basic Info
| Common Name | 1,1-Dimethylbiguanide(F04850) |
| 2D Structure | |
| Description | Metformin is the most popular anti-diabetic drug in the United States and one of the most prescribed drugs in the country overall, with nearly 35 million prescriptions filled in 2006 for generic metformin alone. Metformin is a biguanide antihyperglycemic agent used for treating non-insulin-dependent diabetes mellitus (NIDDM). It improves glycemic control by decreasing hepatic glucose production, decreasing glucose absorption and increasing insulin-mediated glucose uptake. Metformin is the only oral antihyperglycemic agent that is not associated with weight gain. Metformin may induce weight loss and is the drug of choice for obese NIDDM patients. When used alone, metformin does not cause hypoglycemia; however, it may potentiate the hypoglycemic effects of sulfonylureas and insulin. Its main side effects are dyspepsia, nausea and diarrhea. Dose titration and/or use of smaller divided doses may decrease side effects. Metformin should be avoided in those with severely compromised renal function (creatinine clearance < 30 ml/min), acute/decompensated heart failure, severe liver disease and for 48 hours after the use of iodinated contrast dyes due to the risk of lactic acidosis. Lower doses should be used in the elderly and those with decreased renal function. Metformin decreases fasting plasma glucose, postprandial blood glucose and glycosolated hemoglobin (HbA1c) levels, which are reflective of the last 8-10 weeks of glucose control. Metformin may also have a positive effect on lipid levels. In 2012, a combination tablet of linagliptin plus metformin hydrochloride was marketed under the name Jentadueto for use in patients when treatment with both linagliptin and metformin is appropriate. |
| FRCD ID | F04850 |
| CAS Number | 657-24-9 |
| PubChem CID | 4091 |
| Formula | C4H11N5 |
| IUPAC Name | 3-(diaminomethylidene)-1,1-dimethylguanidine |
| InChI Key | XZWYZXLIPXDOLR-UHFFFAOYSA-N |
| InChI | InChI=1S/C4H11N5/c1-9(2)4(7)8-3(5)6/h1-2H3,(H5,5,6,7,8) |
| Canonical SMILES | CN(C)C(=N)N=C(N)N |
| Isomeric SMILES | CN(C)C(=N)N=C(N)N |
| Wikipedia | 1,1-Dimethylbiguanide |
| Synonyms |
metformin
657-24-9
1,1-Dimethylbiguanide
Metiguanide
Dimethylbiguanide
Glucophage
Haurymelin
Fluamine
Flumamine
Gliguanid
|
| Classifies |
Predicted: Illegal Additives
|
| Update Date | Nov 13, 2018 17:07 |
Chemical Taxonomy
| Kingdom | Organic compounds |
| Superclass | Organic nitrogen compounds |
| Class | Organonitrogen compounds |
| Subclass | Guanidines |
| Intermediate Tree Nodes | Not available |
| Direct Parent | Biguanides |
| Alternative Parents | |
| Molecular Framework | Aliphatic acyclic compounds |
| Substituents | Biguanide - Organic 1,3-dipolar compound - Propargyl-type 1,3-dipolar organic compound - Carboximidamide - Organopnictogen compound - Hydrocarbon derivative - Imine - Aliphatic acyclic compound |
| Description | This compound belongs to the class of organic compounds known as biguanides. These are organic compounds containing two N-linked guanidines. |
Properties
| Property Name | Property Value |
|---|---|
| Molecular Weight | 129.167 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 1 |
| Rotatable Bond Count | 2 |
| Complexity | 132 |
| Monoisotopic Mass | 129.101 |
| Exact Mass | 129.101 |
| XLogP | -1.3 |
| Formal Charge | 0 |
| Heavy Atom Count | 9 |
| Defined Atom Stereocenter Count | 0 |
| Undefined Atom Stereocenter Count | 0 |
| Defined Bond Stereocenter Count | 0 |
| Undefined Bond Stereocenter Count | 0 |
| Isotope Atom Count | 0 |
| Covalently-Bonded Unit Count | 1 |
ADMET
| Model | Result | Probability |
|---|---|---|
| Absorption | ||
| Blood-Brain Barrier | BBB+ | 0.5868 |
| Human Intestinal Absorption | HIA+ | 0.9156 |
| Caco-2 Permeability | Caco2- | 0.8958 |
| P-glycoprotein Substrate | Non-substrate | 0.6643 |
| P-glycoprotein Inhibitor | Non-inhibitor | 0.9613 |
| Non-inhibitor | 0.8892 | |
| Renal Organic Cation Transporter | Non-inhibitor | 0.7518 |
| Distribution | ||
| Subcellular localization | Lysosome | 0.7916 |
| Metabolism | ||
| CYP450 2C9 Substrate | Non-substrate | 0.7929 |
| CYP450 2D6 Substrate | Non-substrate | 0.7325 |
| CYP450 3A4 Substrate | Non-substrate | 0.6906 |
| CYP450 1A2 Inhibitor | Non-inhibitor | 0.9046 |
| CYP450 2C9 Inhibitor | Non-inhibitor | 0.9159 |
| CYP450 2D6 Inhibitor | Non-inhibitor | 0.9231 |
| CYP450 2C19 Inhibitor | Non-inhibitor | 0.9130 |
| CYP450 3A4 Inhibitor | Non-inhibitor | 0.9506 |
| CYP Inhibitory Promiscuity | Low CYP Inhibitory Promiscuity | 0.9763 |
| Excretion | ||
| Toxicity | ||
| Human Ether-a-go-go-Related Gene Inhibition | Weak inhibitor | 0.9807 |
| Non-inhibitor | 0.9274 | |
| AMES Toxicity | Non AMES toxic | 0.7367 |
| Carcinogens | Non-carcinogens | 0.6691 |
| Fish Toxicity | Low FHMT | 0.8761 |
| Tetrahymena Pyriformis Toxicity | Low TPT | 0.9005 |
| Honey Bee Toxicity | Low HBT | 0.5816 |
| Biodegradation | Not ready biodegradable | 0.9380 |
| Acute Oral Toxicity | III | 0.7817 |
| Carcinogenicity (Three-class) | Non-required | 0.6357 |
| Model | Value | Unit |
|---|---|---|
| Absorption | ||
| Aqueous solubility | -0.9180 | LogS |
| Caco-2 Permeability | 0.2041 | LogPapp, cm/s |
| Distribution | ||
| Metabolism | ||
| Excretion | ||
| Toxicity | ||
| Rat Acute Toxicity | 1.7407 | LD50, mol/kg |
| Fish Toxicity | 2.2781 | pLC50, mg/L |
| Tetrahymena Pyriformis Toxicity | -0.6614 | pIGC50, ug/L |
References
| Title | Journal | Date | Pubmed ID |
|---|---|---|---|
| ITC Commentary on Metformin Clinical Drug-Drug Interaction Study Design That Enables an Efficacy- and Safety-Based Dose Adjustment Decision. | Clin Pharmacol Ther | 2018 Nov | 29761830 |
| Antihyperglycemic and anti-inflammatory effects of fermented food paste inhigh-fat diet and streptozotocin-challenged mice. | Drug Des Devel Ther | 2018 May 23 | 29872261 |
| Bis-Indole-Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent GlucoseMetabolism and Uptake in C2C12 Cells. | Endocrinology | 2018 May 1 | 29635345 |
| Is metformin poised for a second career as an antimicrobial? | Diabetes Metab Res Rev | 2018 May | 29271563 |
| A novel biocompatible NiII tethered moiety as a glucose uptake agent and a hitagainst methicillin-resistant Staphylococcus aureus. | Eur J Pharm Sci | 2018 Jul 5 | 29981891 |
| Antidiabetic activities of entagenic acid in type 2 diabetic db/db mice and L6myotubes via AMPK/GLUT4 pathway. | J Ethnopharmacol | 2018 Jan 30 | 28993280 |
| High amylose starch consumption induces obesity in Drosophila melanogaster andmetformin partially prevents accumulation of storage lipids and shortens lifespanof the insects. | Comp Biochem Physiol A Mol Integr Physiol | 2018 Jan | 29054808 |
| Identification of the signals for glucose-induced insulin secretion in INS1(832/13) β-cells using metformin-induced metabolic deceleration as a model. | J Biol Chem | 2017 Nov 24 | 28972173 |
| Towards natural mimetics of metformin and rapamycin. | Aging (Albany NY) | 2017 Nov 15 | 29165314 |
| Effect of Cichorium intybus L. seed extract on renal parameters in experimentallyinduced early and late diabetes type 2 in rats. | Ren Fail | 2017 Nov | 27846769 |
| Occurrence of pharmaceuticals and personal care products in effluent-dominatedSaudi Arabian coastal waters of the Red Sea. | Chemosphere | 2017 May | 28249192 |
| mTORC1 inhibitors rapamycin and metformin affect cardiovascular markersdifferentially in ZDF rats. | Can J Physiol Pharmacol | 2017 Mar | 28177677 |
| A role for <i>PFKFB3</i>/iPFK2 in metformin suppression of adipocyte inflammatory responses. | J Mol Endocrinol | 2017 Jul | 28559290 |
| Aspalathin Protects the Heart against Hyperglycemia-Induced Oxidative Damage byUp-Regulating Nrf2 Expression. | Molecules | 2017 Jan 14 | 28098811 |
| A model of type 2 diabetes in the guinea pig using sequential diet-inducedglucose intolerance and streptozotocin treatment. | Dis Model Mech | 2017 Feb 1 | 28093504 |
| Hybrid drug combination: Combination of ferulic acid and metformin asanti-diabetic therapy. | Phytomedicine | 2017 Dec 15 | 29126698 |
| Cucurbitane glycosides from the fruit of Siraitia grosvenori and their effects onglucose uptake in human HepG2 cells in vitro. | Food Chem | 2017 Aug 1 | 28317764 |
| Postmeal exercise blunts postprandial glucose excursions in people on metforminmonotherapy. | J Appl Physiol (1985) | 2017 Aug 1 | 28522762 |
| PGC1α Activators Mitigate Diabetic Tubulopathy by Improving MitochondrialDynamics and Quality Control. | J Diabetes Res | 2017 | 28409163 |
| Antidiabetic (type 2) effects of Lactobacillus G15 and Q14 in rats throughregulation of intestinal permeability and microbiota. | Food Funct | 2016 Sep 14 | 27713957 |
Targets
- General Function:
- Virus receptor activity
- Specific Function:
- Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. Acts as a positive regulator of T-cell coactivation, by binding at least ADA, CAV1, IGF2R, and PTPRC. Its binding to CAV1 and CARD11 induces T-cell proliferation and NF-kappa-B activation in a T-cell receptor/CD3-dependent manner. Its interaction with ADA also regulates lymphocyte-epithelial cell adhesion. In association with FAP is involved in the pericellular proteolysis of the extracellular matrix (ECM), the migration and invasion of endothelial cells into the ECM. May be involved in the promotion of lymphatic endothelial cells adhesion, migration and tube formation. When overexpressed, enhanced cell proliferation, a process inhibited by GPC3. Acts also as a serine exopeptidase with a dipeptidyl peptidase activity that regulates various physiological processes by cleaving peptides in the circulation, including many chemokines, mitogenic growth factors, neuropeptides and peptide hormones. Removes N-terminal dipeptides sequentially from polypeptides having unsubstituted N-termini provided that the penultimate residue is proline.
- Gene Name:
- DPP4
- Uniprot ID:
- P27487
- Molecular Weight:
- 88277.935 Da
References
- Taldone T, Zito SW, Talele TT: Inhibition of dipeptidyl peptidase-IV (DPP-IV) by atorvastatin. Bioorg Med Chem Lett. 2008 Jan 15;18(2):479-84. Epub 2007 Dec 3. [18068977 ]
- General Function:
- Secondary active organic cation transmembrane transporter activity
- Specific Function:
- Translocates a broad array of organic cations with various structures and molecular weights including the model compounds 1-methyl-4-phenylpyridinium (MPP), tetraethylammonium (TEA), N-1-methylnicotinamide (NMN), 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP), the endogenous compounds choline, guanidine, histamine, epinephrine, adrenaline, noradrenaline and dopamine, and the drugs quinine, and metformin. The transport of organic cations is inhibited by a broad array of compounds like tetramethylammonium (TMA), cocaine, lidocaine, NMDA receptor antagonists, atropine, prazosin, cimetidine, TEA and NMN, guanidine, cimetidine, choline, procainamide, quinine, tetrabutylammonium, and tetrapentylammonium. Translocates organic cations in an electrogenic and pH-independent manner. Translocates organic cations across the plasma membrane in both directions. Transports the polyamines spermine and spermidine. Transports pramipexole across the basolateral membrane of the proximal tubular epithelial cells. The choline transport is activated by MMTS. Regulated by various intracellular signaling pathways including inhibition by protein kinase A activation, and endogenously activation by the calmodulin complex, the calmodulin-dependent kinase II and LCK tyrosine kinase.
- Gene Name:
- SLC22A1
- Uniprot ID:
- O15245
- Molecular Weight:
- 61153.345 Da
References
- Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM: Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res. 2002 Aug;19(8):1244-7. [12240953 ]
- General Function:
- Quaternary ammonium group transmembrane transporter activity
- Specific Function:
- Mediates tubular uptake of organic compounds from circulation. Mediates the influx of agmatine, dopamine, noradrenaline (norepinephrine), serotonin, choline, famotidine, ranitidine, histamin, creatinine, amantadine, memantine, acriflavine, 4-[4-(dimethylamino)-styryl]-N-methylpyridinium ASP, amiloride, metformin, N-1-methylnicotinamide (NMN), tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, cisplatin and oxaliplatin. Cisplatin may develop a nephrotoxic action. Transport of creatinine is inhibited by fluoroquinolones such as DX-619 and LVFX. This transporter is a major determinant of the anticancer activity of oxaliplatin and may contribute to antitumor specificity.
- Gene Name:
- SLC22A2
- Uniprot ID:
- O15244
- Molecular Weight:
- 62579.99 Da
References
- Dresser MJ, Xiao G, Leabman MK, Gray AT, Giacomini KM: Interactions of n-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2). Pharm Res. 2002 Aug;19(8):1244-7. [12240953 ]
- General Function:
- Protein kinase activity
- Specific Function:
- Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).
- Gene Name:
- PRKAB1
- Uniprot ID:
- Q9Y478
- Molecular Weight:
- 30382.085 Da
- Mechanism of Action:
- Metformin's pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
References
- Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR: Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem. 2003 Oct 10;278(41):39422-7. Epub 2003 Jul 29. [12890675 ]