PHENFORMIN

US Previously Marketed

First approved in 1959

Details

Stereochemistry	ACHIRAL
Molecular Formula	C10H15N5
Molecular Weight	205.26
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

c1ccc(cc1)CCNC(=N)NC(=N)N

InChI

InChIKey=ICFJFFQQTFMIBG-UHFFFAOYSA-N

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)

HIDE SMILES / InChI

Molecular Formula	C10H15N5
Molecular Weight	205.26
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.druglib.com/activeingredient/phenformin/ | https://www.ncbi.nlm.nih.gov/pubmed/9848705 | https://www.ncbi.nlm.nih.gov/pubmed/20444419 | https://www.ncbi.nlm.nih.gov/pubmed/25511514

Phenformin is a biguanide hypoglycemic agent with actions and uses similar to those of metformin. It activates AMP-activated protein kinase (AMPK) and inhibits mTORC1 signaling. Phenformin used for the treatment of diabetes. Phenformin was removed from the U.S. market 20 years ago because of a high incidence of lactic acidosis. Risk factors for the development of lactic acidosis include renal deficiency, hepatic disease, cardiac disease, and drug interaction such as cimetidine. Phenformin exerts potential anti-neoplastic action.

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
AMP-activated protein kinase, AMPK 16 Target ID: CHEMBL2096907 Sources: https://www.ncbi.nlm.nih.gov/pubmed/29245964 \| https://www.ncbi.nlm.nih.gov/pubmed/14976552	Activator 1335
Monoamine oxidase A 48 Target ID: CHEMBL1951 Sources: https://www.ncbi.nlm.nih.gov/pubmed/24307270	Inhibitor 7701	41 µM [IC50]
Sulfonylurea receptors; K-ATP channels 11 Target ID: CHEMBL2095152 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20188727	Blocker 504
Mammalian target of Rapamycin (mTORC1) 21 Target ID: CHEMBL2221341 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20444419	Inhibitor 7701

Conditions

Condition	Modality	Highest Phase	Product
Ovarian cancer 144 Sources: https://www.ncbi.nlm.nih.gov/pubmed/29245964	Primary	Preclinical
Breast cancer 411 Sources: https://www.ncbi.nlm.nih.gov/pubmed/26114294	Primary	Preclinical
Type 2 diabetes mellitus 240 Sources: https://www.ndrugs.com/?s=phenformin http://www.druglib.com/activeingredient/phenformin/ https://www.drugs.com/international/phenformin.html	Primary	Approved 7997	INFORMIN Approved Use For the treatment of type II diabetes mellitus.
Melanoma 81 Sources: https://www.ncbi.nlm.nih.gov/pubmed/28433543	Primary	Phase I 593

T_1/2

Value	Dose	Co-administered	Analyte	Population
11 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1133221/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENFORMIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

F_unbound

Value	Dose	Co-administered	Analyte	Population
81% EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/1133221/	100 mg single, oral dose: 100 mg route of administration: Oral experiment type: SINGLE co-administered:		PHENFORMIN plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	Disc. AE: Nausea, Vomiting... AEs leading to discontinuation/dose reduction: Nausea Vomiting Anxiety Agitation Polydipsia Polyuria Increased appetite Tachycardia Tachypnea Lactic acidosis Hypoglycemia Hypokalemia Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
400 mg 2 times / day multiple, oral Recommended Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://www.mims.com/philippines/drug/info/phenformin?mtype=generic	unhealthy Health Status: unhealthy Sources: https://www.mims.com/philippines/drug/info/phenformin?mtype=generic	Disc. AE: Lactic acidosis... AEs leading to discontinuation/dose reduction: Lactic acidosis Sources: https://www.mims.com/philippines/drug/info/phenformin?mtype=generic

AEs

AE	Significance	Dose	Population
Agitation	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Anxiety	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Hypoglycemia	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Hypokalemia	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Increased appetite	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Lactic acidosis	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Nausea	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Polydipsia	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Polyuria	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Tachycardia	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Tachypnea	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Vomiting	Disc. AE	2500 mg single, oral Overdose Dose: 2500 mg Route: oral Route: single Dose: 2500 mg Sources: https://pubmed.ncbi.nlm.nih.gov/1020609	healthy Health Status: healthy Sex: F Sources: https://pubmed.ncbi.nlm.nih.gov/1020609
Lactic acidosis	Disc. AE	400 mg 2 times / day multiple, oral Recommended Dose: 400 mg, 2 times / day Route: oral Route: multiple Dose: 400 mg, 2 times / day Sources: https://www.mims.com/philippines/drug/info/phenformin?mtype=generic	unhealthy Health Status: unhealthy Sources: https://www.mims.com/philippines/drug/info/phenformin?mtype=generic

Overview

CYP3A4	CYP2C9	CYP2D6	hERG
		substrate 1038	supressor 9

OverviewOther

Other Inhibitor	Other Substrate	Other Inducer
	P-gp 1223 hOCT1 4

Drug as victim

Target	Modality	Activity
CYP2D6 1038	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/1293869/	yes
P-gp 1223	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/26797108/	yes
hOCT1 4	substrate 2752 Sources: https://pubmed.ncbi.nlm.nih.gov/19768675/	yes

Tox targets

Target	Modality	Activity	Metabolite	Clinical evidence
hERG 1392	supressor 9 Sources: https://pubmed.ncbi.nlm.nih.gov/23716168/

Sourcing

Vendor/Aggregator	ID	URL
PubChem	13266	https://pubchem.ncbi.nlm.nih.gov/compound/13266

PubMed

Title	Date	PubMed
Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus.	2003	12804446
Effects of phenformin on the proliferation of human tumor cell lines.	2003 Dec 19	14623034
Activity of LKB1 and AMPK-related kinases in skeletal muscle: effects of contraction, phenformin, and AICAR.	2004 Aug	15068958
N-bromosuccinimide-fluorescein based sensitive flow-injection chemiluminescence determination of phenformin.	2004 Feb	15055959
Molecularly imprinted solid-phase extraction for the screening of antihyperglycemic biguanides.	2004 Feb 20	14971497
LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1.	2004 Feb 25	14976552
All-cause mortality in diabetic patients treated with combinations of sulfonylureas and biguanides.	2004 Jan-Feb	14737744
[Lactic acidosis in diabetic patient treated with metformin].	2004 Jun	15283644
A convenient five-drug cocktail for the assessment of major drug metabolizing enzymes: a pilot study.	2004 Sep	15327588
Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitation of metformin in human plasma.	2004 Sep 5	15261814
Phenformin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) activation of AMP-activated protein kinase inhibits transepithelial Na+ transport across H441 lung cells.	2005 Aug 1	15919715
Metformin reduces adiponectin protein expression and release in 3T3-L1 adipocytes involving activation of AMP activated protein kinase.	2005 Aug 22	16039647
Contraindications can damage your health--is metformin a case in point?	2005 Dec	16283245
Does AMP-activated protein kinase couple inhibition of mitochondrial oxidative phosphorylation by hypoxia to calcium signaling in O2-sensing cells?	2005 Dec 16	16199527
Metformin transport by renal basolateral organic cation transporter hOCT2.	2005 Feb	15783073
Metabolic activation of AMP kinase in vascular smooth muscle.	2005 Jan	15377643
Effects of phentermine and phenformin on biomarkers of aging in rats.	2005 Jan-Feb	15591752
Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes.	2005 Jul 1	15878856
Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction.	2005 May 18	15889149
Acute renal ischemia rapidly activates the energy sensor AMPK but does not increase phosphorylation of eNOS-Ser1177.	2005 Nov	15914772
Identification of potential caloric restriction mimetics by microarray profiling.	2005 Nov 17	16189280
HIV/AIDS in older adults: a case report and literature review.	2005 Sep	16153142
Drug-induced pancreatitis: an update.	2005 Sep	16082282
Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis).	2006 Apr	16567854
LKB1, an upstream AMPK kinase, regulates glucose and lipid metabolism in cultured liver and muscle cells.	2006 Dec 22	17083919
Activators of the energy sensing kinase AMPK inhibit random cell movement and chemotaxis in U937 cells.	2006 Feb	16405649
AMP-activated protein kinase (AMPK) activating agents cause dephosphorylation of Akt and glycogen synthase kinase-3.	2006 May 28	16620785
Muscle-specific overexpression of wild type and R225Q mutant AMP-activated protein kinase gamma3-subunit differentially regulates glycogen accumulation.	2006 Sep	16638825
[Diabetic lactic acidosis].	2006 Sep 28	17022521
The phase shift hypothesis for the circadian component of winter depression.	2007	17969866
The role of mitochondria in protection of the heart by preconditioning.	2007 Aug	17631856
Simultaneous determination of metformin and rosiglitazone in human plasma by liquid chromatography/tandem mass spectrometry with electrospray ionization: application to a pharmacokinetic study.	2007 Jul 1	17459785
Cellular and molecular mechanisms in the long-term action of antidepressants.	2008	19170396
Comparison of gene expression changes induced by biguanides in db/db mice liver.	2008 Aug	18670165
Mechanisms of myocyte cytotoxicity induced by the multiple receptor tyrosine kinase inhibitor sunitinib.	2008 Dec	18815214
Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle.	2008 Dec	18796617
Older age and phenformin therapy: a dangerous association.	2008 Dec	18415028
[Experimental studies on hypoglycemic effects of total flavonoid from Toona sinensis].	2008 Nov	19260289
AICAR decreases the activity of two distinct amiloride-sensitive Na+-permeable channels in H441 human lung epithelial cell monolayers.	2008 Nov	18723760
Uncoupling of the LKB1-AMPKalpha energy sensor pathway by growth factors and oncogenic BRAF.	2009	19274086
AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease.	2009 Apr	19275766
Adenylate kinase and AMP signaling networks: metabolic monitoring, signal communication and body energy sensing.	2009 Apr 17	19468337
High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.	2009 Apr 21	19349317
Simultaneous determination of anti-diabetes/anti-obesity drugs by LC/PDA, and targeted analysis of sibutramine analog in dietary supplements by LC/MS/MS.	2009 Dec	19475544
C-terminal phosphorylation of LKB1 is not required for regulation of AMP-activated protein kinase, BRSK1, BRSK2, or cell cycle arrest.	2009 Jan 2	18854318
Quasi-equilibrium analysis of the ion-pair mediated membrane transport of low-permeability drugs.	2009 Jul 1	19264104
Regulation of Cl(-) secretion by AMPK in vivo.	2009 Mar	18752001
Mood, side-effects and smoking outcomes among persons with and without probable lifetime depression taking varenicline.	2009 May	19238488
Chemical genomics identifies the unfolded protein response as a target for selective cancer cell killing during glucose deprivation.	2009 May 15	19435925
Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization.	2009 Sep	19502419

Patents

Sample Use Guides

In Vivo Use Guide

200-400 mg bid.

Route of Administration: Oral

In Vitro Use Guide

To evaluate the underlying mechanism of growth inhibition by phenformin, the cell cycle profile was analyzed after treating the SKOV3, Hey and IGROV-1 cell lines with varying doses (0.01-2.5 mM) of phenformin for 24 hours. Phenformin induced G0/G1 cell cycle arrest and reduced S phase in the Hey and SKOV3 OC cell lines and increased G2 phase in the IGROV-1 OC cell line in a dose-dependent manner.

Substance Class	Chemical Created by `admin` on `Sat Jun 26 11:21:03 UTC 2021` Edited by `admin` on `Sat Jun 26 11:21:03 UTC 2021`
Record UNII	DD5K7529CE
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PHENFORMIN

Official Name

English

PHENFORMIN [INN]

Common Name

English

PHENFORMIN [MI]

Common Name

English

PHENFORMIN [HSDB]

Common Name

English

PHENFORMIN [WHO-DD]

Common Name

English

IMIDODICARBONIMIDIC DIAMIDE, N-(2-PHENYLETHYL)-

Systematic Name

English

PHENFORMIN [VANDF]

Common Name

English

Classification Tree Code System Code

WHO-VATC

QA10BD01