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Identification
Name Phenformin
Accession Number DB00914 (APRD00511)
Type small molecule
Groups approved, withdrawn
Description

A biguanide hypoglycemic agent with actions and uses similar to those of metformin. Although it is generally considered to be associated with an unacceptably high incidence of lactic acidosis, often fatal, it is still available in some countries. (From Martindale, The Extra Pharmacopoeia, 30th ed, p290)
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
  • Beta-Pebg
  • Beta-Phenethybiguanide
  • Beta-Phenethylbiguanide
  • Fenformin
  • Fenformina [INN-Spanish]
  • N-Phenethylbiguanide Hydrochloride
  • PEDG
  • Phenethylbiguanide Hydrochloride
  • Phenethyldiguanide
  • Phenformin HCl
  • Phenformin Hydrochloride
  • Phenformine
  • Phenformine [INN-French]
  • Phenformine HCl
  • Phenforminum [INN-Latin]
  • Phenoformine Hydrochloride
  • Phenylethylbiguanide
Synonyms
Beta-Pebg
Beta-Phenethybiguanide
Beta-Phenethylbiguanide
Fenformin
Fenformina [INN-Spanish]
N-Phenethylbiguanide Hydrochloride
PEDG
Phenethylbiguanide Hydrochloride
Phenethyldiguanide
Phenformin HCl
Phenformin Hydrochloride
Phenformine
Phenformine [INN-French]
Phenformine HCl
Phenforminum [INN-Latin]
Phenoformine Hydrochloride
Phenylethylbiguanide
First Prev Next Last
Salts Not Available
Brand names
Name Company
Azucaps
Cronoformin
D Bretard
DB Comb
DB-Retard
DBI
DBI Monohydrochloride
Debeone
Debinyl
Diabis
Dibein
Dibiraf
Dibotin
Dipar
Feguanide
Fenfoduron
Fenormin
Glukopostin
Glyphen
Insoral
Lentobetic
Meltrol
Meltrol-50
Normoglucina
Phenformix
Retardo
First Prev Next Last
Brand mixtures Not Available
Categories
  • Hypoglycemic Agents
CAS number 114-86-3
Weight Average: 205.2596
Monoisotopic: 205.132745505
Chemical Formula C10H15N5
InChI Key InChIKey=ICFJFFQQTFMIBG-UHFFFAOYSA-N
InChI
InChI=1S/C10H15N5/c11-9(12)15-10(13)14-7-6-8-4-2-1-3-5-8/h1-5H,6-7H2,(H6,11,12,13,14,15)
Plain Text
IUPAC Name
1-carbamimidamido-N-(2-phenylethyl)methanimidamide
SMILES
NC(=N)NC(=N)NCCC1=CC=CC=C1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes
  • Phenethylamines
Substructures
  • Benzene and Derivatives
  • Biguanides
  • Phenethylamines
  • Guanidines
  • Aromatic compounds
  • Carboxamidines
Pharmacology
Indication For the reatment of type II diabetes mellitus.
Pharmacodynamics Used to treat diabetes, phenformin is a biguanide (contains 2 guanidino groups) hypoglycemic agent with actions and uses similar to those of metformin (Glucophage). Both drugs work by (1) decreasing the absorption of glucose by the intestines, (2) decreasing the production of glucose in the liver, and by (3) increasing the body's ability to use insulin more effectively. More specifically, phenformin improves glycemic control by improving insulin sensitivity. Phenformin is generally considered to be associated with an unacceptably high incidence of actic acidosis. In general biguanides should be used only in stable type II diabetics who are free of liver, kidney and cardiovascular problems and who cannot be controlled with diet.
Mechanism of action Phenformin binds to the AMP-activated protein kinase (AMPK). AMPK is an ultra-sensitive cellular energy sensor that monitors energy consumption and down-regulates ATP-consuming processes when activated. The biguanide phenformin has been shown to independently decrease ion transport processes, influence cellular metabolism and activate AMPK. Phenformin's hypoglycemic activity is related the effect it has in activating AMPK and fooling insulin sensitive cells into thinking that insulin levels are low and causing the body to use glucose as if in a state of low caloric consumption. This drug also seems to inhibit several varients of ATP-sensitive potassium channels (namely the receptor subtype Kir6.1).
Absorption Not Available
Volume of distribution Not Available
Protein binding Not Available
Metabolism Not Available
Route of elimination Not Available
Half life Not Available
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers Not Available
Packagers Not Available
Dosage forms Not Available
Prices Not Available
Patents Not Available
Properties
State solid
Melting point 175-178 oC
Experimental Properties
Property Value Source
water solubility 210 mg/mL PhysProp
logP 0.1 PhysProp
Predicted Properties
Property Value Source
water solubility 2.32e-01 g/l ALOGPS
logP -0.72 ALOGPS
logP 0.83 ChemAxon Molconvert
logS -3 ALOGPS
pKa 0 ChemAxon Molconvert
hydrogen acceptor count 5 ChemAxon Molconvert
hydrogen donor count 5 ChemAxon Molconvert
polar surface area 97.78 ChemAxon Molconvert
rotatable bond count 3 ChemAxon Molconvert
refractivity 80.72 ChemAxon Molconvert
polarizability 22.14 ChemAxon Molconvert
References
Synthesis Reference Not Available
General Reference
  1. Enia G, Garozzo M, Zoccali C: Lactic acidosis induced by phenformin is still a public health problem in Italy. BMJ. 1997 Nov 29;315(7120):1466-7. Pubmed
  2. Rosand J, Friedberg JW, Yang JM: Fatal phenformin-associated lactic acidosis. Ann Intern Med. 1997 Jul 15;127(2):170. Pubmed
External Links
Resource Link
KEGG Compound C07673 Link_out
PubChem Compound 8249 Link_out
PubChem Substance 46505230 Link_out
ChemSpider 7953 Link_out
BindingDB 50240908 Link_out
Therapeutic Targets Database DAP000206 Link_out
PharmGKB PA1000 Link_out
Wikipedia http://en.wikipedia.org/wiki/Phenformin Link_out
ATC Codes
  • A10BA01
AHFS Codes Not Available
PDB Entries Not Available
FDA label Not Available
MSDS Not Available
Interactions
Drug Interactions Not Available
Food Interactions Not Available
Targets

1. 5'-AMP-activated protein kinase catalytic subunit alpha-1

Pharmacological action: yes
Actions: activator

Responsible for the regulation of fatty acid synthesis by phosphorylation of acetyl-CoA carboxylase. It also regulates cholesterol synthesis via phosphorylation and inactivation of hormone-sensitive lipase and hydroxymethylglutaryl-CoA reductase. Appears to act as a metabolic stress-sensing protein kinase switching off biosynthetic pathways when cellular ATP levels are depleted and when 5'-AMP rises in response to fuel limitation and/or hypoxia. This is a catalytic subunit

Organism class: human
UniProt ID: Q13131 Link_out
Gene: PRKAA1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Woollhead AM, Sivagnanasundaram J, Kalsi KK, Pucovsky V, Pellatt LJ, Scott JW, Mustard KJ, Hardie DG, Baines DL: Pharmacological activators of AMP-activated protein kinase have different effects on Na+ transport processes across human lung epithelial cells. Br J Pharmacol. 2007 Aug;151(8):1204-15. Epub 2007 Jul 2. Pubmed
  2. Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C: Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008 Jan 15;409(2):449-59. Pubmed
  3. Zhang L, He H, Balschi JA: Metformin and phenformin activate AMP-activated protein kinase in the heart by increasing cytosolic AMP concentration. Am J Physiol Heart Circ Physiol. 2007 Jul;293(1):H457-66. Epub 2007 Mar 16. Pubmed

2. ATP-sensitive inward rectifier potassium channel 8

Pharmacological action: unknown
Actions: inhibitor

This potassium channel is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by external barium (By similarity)

Organism class: human
UniProt ID: Q15842 Link_out
Gene: KCNJ8
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Aziz Q, Thomas A, Khambra T, Tinker A: Phenformin has a direct inhibitory effect on the ATP-sensitive potassium channel. Eur J Pharmacol. 2010 May 25;634(1-3):26-32. Epub 2010 Feb 25. Pubmed
Enzymes

1. Cytochrome P450 2D6

Actions: substrate

Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic antidepressants

UniProt ID: P10635 Link_out
Gene: CYP2D6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
Transporters

1. Solute carrier family 22 member 2

Actions: inhibitor

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

UniProt ID: O15244 Link_out
Gene: SLC22A2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Pubmed

2. Solute carrier family 22 member 1

Actions: substrate, inhibitor

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

UniProt ID: O15245 Link_out
Gene: SLC22A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Pubmed
  2. Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y: Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther. 2002 Aug;302(2):510-5. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 14, 2012 11:44