Fenproporex

Identification

Name
Fenproporex
Accession Number
DB01550
Type
Small Molecule
Groups
Experimental, Illicit, Withdrawn
Description

Fenproporex is an orally active stimulant drug, which was developed in the 1960s. It is used as an appetite suppressant and a treatment for obesity. However, due to an addictive potential, it is listed as an illicit substance in many countries. Structurally, fenproporex (N-2-cyanoethylamphetamine) falls within the phenylethamine and amphetamine chemical class of drugs. The N-2-cyanoethyl substituent was once believed to be resistant to cleavage, because fenproporex -- once recommended as an obesity treatment for patients with cardiovascular disease -- was originally claimed to lack stimulant properties. Contrary to the claim, research has demonstrated easy in vivo cleavage of the N-2-cyanothyl substituent to yield amphetamine as a metabolite. [5] However, in clinical practice, central nervous system stimulative effects are less notorious than with some other agents such as diethylpropion and mazindol. [7]

In the United States fenproporex was never approved by the FDA for clinical use due to a lack of efficacy and safety data, and is listed as a drug in Schedule IV of the Controlled Substances Act. In 2006 and 2009, the FDA issued warnings that it had been detected in diet pills sold online, and imported from foreign manufacturers. It is also listed as a prohibited substance by the World Anti-Doping Agency. [Wikipedia]

Despite being banned in the United States, fenproporex has been described as the second most commonly consumed appetite suppressant worldwide, [6] with fenproporex containing anorectics still being commonly prescribed in South America. Little is known about the specific hazards of amphetamine based diet pills, however case reports have noted side effects such as chest pain, palpitations, headaches, and insomnia. In addition, placebo controlled studies have shown that participants using fenproporex experience more joint pain, sweating, blurred vision and tremor. [2]

Structure
Thumb
Synonyms
  • Fenorex
  • Perphoxene
International/Other Brands
Desobesi-M (Aché) / Feprorex (Medix) / Lipenan (Sanofi-Aventis) / Salcal (Saval)
Categories
UNII
W0194S5FOA
CAS number
16397-28-7
Weight
Average: 188.2688
Monoisotopic: 188.131348522
Chemical Formula
C12H16N2
InChI Key
IQUFSXIQAFPIMR-UHFFFAOYSA-N
InChI
InChI=1S/C12H16N2/c1-11(14-9-5-8-13)10-12-6-3-2-4-7-12/h2-4,6-7,11,14H,5,9-10H2,1H3
IUPAC Name
3-[(1-phenylpropan-2-yl)amino]propanenitrile
SMILES
CC(CC1=CC=CC=C1)NCCC#N

Pharmacology

Indication

Fenproporex is used as an appetite suppressant, and anti-obesity agent [2]; however, due to substance abuse potential, it is an illicit substance in many countries. In some countries, such as Brazil, it is still prescribed -- often in the form of diet pills (ie. Brazilian Diet Pills) which combine amphetamines, benzodiazepines, antidepressants, diuretics and laxatives.

In the United States the sale of such diet pills has been banned due to concerns over side effects, and the risk of potentially fatal overdose. However, internet sales and illicit markets has lead to international availability. It has been found by primary care physicians that Brazilian immigrant women utilized imported diet pills at particularly high rates, and sometimes suffered from side effects requiring hospitalization or experienced a loss of employment. [3]

Pharmacodynamics

Fenproporex was first claimed to not exert a stimulant effect on the body, however research into its metabolism has shown that it is converted into a considerable amount of amphetamine in the body, which leads to stimulant effects. [9]

Mechanism of action

Fenproporex is an amphetamine based anorectic which is rapidly metabolized into amphetamine in the body. Both acute and chronic fenproporex administration has been shown to increase brain energy metabolism in young rats, by increasing the activity of citrate synthase, malate dehydrogenase, succinate dehydrogenase, creatine kinase and complexes I,II, III, and IV. [8]

Amphetamine based drugs are also known to reduce food intake. They are addictive substances due to their ability to increase dopamine release, however their anorectic effects are believed to be a result of noradrenergic neurotransmission. Activation of the alpha 1 and beta 2 adrenoceptors has been shown to decrease food intake, and drugs which release norepinephrine or block norepinephrine reuptake can activate these receptors. [3]

The alpha 1 and beta 2 adrenoceptors are noted to be clinically important receptors in weight regulation. [3]

Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

A large portion, 60-80%, of fenproporex is rapidly converted into amphetamine. Besides amphetamine, and unchanged fenproporex, 14 other metabolites were identified from urine samples.

Two interacting metabolic pathways are believed to exist. The major pathway is believed to involve ring-degradation by aromatic hydroxylation, methylation, and side chain degradation by N-dealkyation to form amphetamine. The minor pathway involves the beta-hydroxylation of amphetamine to form norephedrine. [6]

Route of elimination

Renally eliminated in the urine, mainly as amphetamine, but 5-9% as unchanged drug.

Half life
Not Available
Clearance

The amphetamine metabolite can be detected for several days after the administration of forproporex (up to 119h, in one study). [2]

Toxicity
Not Available
Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AcarboseAcarbose may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AcetaminophenAcetaminophen may decrease the excretion rate of Fenproporex which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AclidiniumFenproporex may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineFenproporex may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Fenproporex which could result in a higher serum level.
AdefovirAdefovir may decrease the excretion rate of Fenproporex which could result in a higher serum level.
Food Interactions
Not Available

References

Synthesis Reference

Rohrbach, P. and Blum, J.; U.S. Patent 3,485,924; December 23, 1969; assigned to Manufactures J.R. Bottu (France).

US3485924
General References
  1. Bray GA: A concise review on the therapeutics of obesity. Nutrition. 2000 Oct;16(10):953-60. [PubMed:11054601]
  2. Cody JT, Valtier S: Detection of amphetamine following administration of fenproporex. J Anal Toxicol. 1996 Oct;20(6):425-31. [PubMed:8889679]
  3. Cohen PA, McCormick D, Casey C, Dawson GF, Hacker KA: Imported compounded diet pill use among Brazilian women immigrants in the United States. J Immigr Minor Health. 2009 Jun;11(3):229-36. Epub 2007 Dec 9. [PubMed:18066718]
  4. Cohen PA: Imported fenproporex-based diet pills from Brazil: a report of two cases. J Gen Intern Med. 2009 Mar;24(3):430-3. doi: 10.1007/s11606-008-0878-4. [PubMed:19096898]
  5. Coutts RT, Nazarali AJ, Baker GB, Pasutto FM: Metabolism and disposition of N-(2-cyanoethyl)amphetamine (fenproporex) and amphetamine: study in the rat brain. Can J Physiol Pharmacol. 1986 Jun;64(6):724-8. [PubMed:3756624]
  6. Kraemer T, Theis GA, Weber AA, Maurer HH: Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay. J Chromatogr B Biomed Sci Appl. 2000 Jan 28;738(1):107-18. [PubMed:10778932]
  7. Rezin GT, Jeremias IC, Ferreira GK, Cardoso MR, Morais MO, Gomes LM, Martinello OB, Valvassori SS, Quevedo J, Streck EL: Brain energy metabolism is activated after acute and chronic administration of fenproporex in young rats. Int J Dev Neurosci. 2011 Dec;29(8):937-42. doi: 10.1016/j.ijdevneu.2011.06.007. Epub 2011 Jun 23. [PubMed:21723935]
  8. Tognoni G, Morselli PL, Garattini S: Amphetamine concentrations in rat brain and human urine after fenproporex administration. Eur J Pharmacol. 1972 Oct;20(1):125-6. [PubMed:4637940]
  9. Mancini MC, Halpern A: Pharmacological treatment of obesity. Arq Bras Endocrinol Metabol. 2006 Apr;50(2):377-89. Epub 2006 May 23. [PubMed:16767304]
External Links
KEGG Drug
D07947
PubChem Compound
61810
PubChem Substance
46508336
ChemSpider
55690
ChEBI
134837
ChEMBL
CHEMBL2105566
Drugs.com
Drugs.com Drug Page
Wikipedia
Fenproporex

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)146Rohrbach, P. and Blum, J.; U.S. Patent 3,485,924; December 23, 1969; assigned to Manufactures J.R. Bottu (France).
Predicted Properties
PropertyValueSource
Water Solubility0.184 mg/mLALOGPS
logP2.14ALOGPS
logP2.01ChemAxon
logS-3ALOGPS
pKa (Strongest Basic)7.88ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area35.82 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity58.24 m3·mol-1ChemAxon
Polarizability22.04 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.996
Blood Brain Barrier+0.905
Caco-2 permeable+0.7437
P-glycoprotein substrateNon-substrate0.5656
P-glycoprotein inhibitor INon-inhibitor0.6871
P-glycoprotein inhibitor IINon-inhibitor0.773
Renal organic cation transporterInhibitor0.5146
CYP450 2C9 substrateNon-substrate0.7702
CYP450 2D6 substrateSubstrate0.7896
CYP450 3A4 substrateNon-substrate0.7524
CYP450 1A2 substrateInhibitor0.6815
CYP450 2C9 inhibitorNon-inhibitor0.9019
CYP450 2D6 inhibitorNon-inhibitor0.51
CYP450 2C19 inhibitorNon-inhibitor0.6544
CYP450 3A4 inhibitorNon-inhibitor0.703
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8178
Ames testNon AMES toxic0.8702
CarcinogenicityNon-carcinogens0.8414
BiodegradationNot ready biodegradable0.9393
Rat acute toxicity2.1504 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.8172
hERG inhibition (predictor II)Non-inhibitor0.6721
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as amphetamines and derivatives. These are organic compounds containing or derived from 1-phenylpropan-2-amine.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Phenethylamines
Direct Parent
Amphetamines and derivatives
Alternative Parents
Phenylpropanes / Aralkylamines / Nitriles / Dialkylamines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Amphetamine or derivatives / Phenylpropane / Aralkylamine / Secondary amine / Nitrile / Carbonitrile / Secondary aliphatic amine / Organic nitrogen compound / Organopnictogen compound / Hydrocarbon derivative
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Drug created on July 31, 2007 07:10 / Updated on November 02, 2018 05:02