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Identification
NamePerhexiline
Accession NumberDB01074  (APRD00107)
TypeSmall Molecule
GroupsApproved
Description

2-(2,2-Dicyclohexylethyl)piperidine. Coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis. [PubChem]

Structure
Thumb
Synonyms
(-)-2-(2,2-Dicyclohexylethyl)piperidine
(+)-2-(2,2-Dicyclohexylethyl)piperidine
2-(2,2-Dicyclohexylethyl)piperidine
Perhexilene
Perhexilina
Perhexiline
Perhexilinum
Perhexilline
External Identifiers Not Available
Prescription ProductsNot Available
Generic Prescription ProductsNot Available
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
SaltsNot Available
Categories
UNIIKU65374X44
CAS number6621-47-2
WeightAverage: 277.4879
Monoisotopic: 277.276950125
Chemical FormulaC19H35N
InChI KeyInChIKey=CYXKNKQEMFBLER-UHFFFAOYSA-N
InChI
InChI=1S/C19H35N/c1-3-9-16(10-4-1)19(17-11-5-2-6-12-17)15-18-13-7-8-14-20-18/h16-20H,1-15H2
IUPAC Name
2-(2,2-dicyclohexylethyl)piperidine
SMILES
C(C(C1CCCCC1)C1CCCCC1)C1CCCCN1
Taxonomy
DescriptionThis compound belongs to the class of organic compounds known as piperidines. These are compounds containing a piperidine ring, which is a saturated aliphatic six-member ring with one nitrogen atom and five carbon atoms.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassPiperidines
Sub ClassNot Available
Direct ParentPiperidines
Alternative Parents
Substituents
  • Piperidine
  • Azacycle
  • Secondary amine
  • Secondary aliphatic amine
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External DescriptorsNot Available
Pharmacology
IndicationFor the management of severe angina pectoris.
PharmacodynamicsUsed in the treatment of unresponsive or refractory angina. Perhexiline increases glucose metabolism at the expense of free-fatty-acid metabolism, enhancing oxygen efficiency during myocardial ischaemia. Perhexiline also potentiates platelet responsiveness to nitric oxide both in patients with angina and patients with acute coronary syndrome. The predominant mechanism of this particular perhexiline effect is an increase in platelet cGMP responsiveness. Perhexiline also may reduce the potential for nitric oxide clearance by neutrophil-derived oxygen. Perhexiline relieves symptoms of angina, improves exercise tolerance, and increases the workload needed to induce ischaemia when used as monotherapy. The primary therapeutic roles for perhexiline are as short-term therapy (less than 3 months duration) in patients with severe ischaemia awaiting coronary revascularisation or long-term therapy in patients with ischaemic symptoms refractory to other therapeutic measures.
Mechanism of actionPerhexiline binds to the mitochondrial enzyme carnitine palmitoyltransferase (CPT)-1 and CPT-2. It acts by shifting myocardial substrate utilisation from long chain fatty acids to carbohydrates through inhibition of CPT-1 and, to a lesser extent, CPT-2, resulting in increased glucose and lactate utilization. This results in increased ATP production for the same O2 consumption as before and consequently increases myocardial efficiency.
Related Articles
AbsorptionWell absorbed (>80%) from the gastrointestinal tract following oral administration.
Volume of distributionNot Available
Protein bindingPerhexiline and its metabolites are highly protein bound (>90%).
Metabolism

The principal metabolites of perhexiline in man are monohydroxyperhexiline (which is excreted, in part, conjugated with glucuronic acid) and dihydroxyperhexiline that accounts for a relatively small proportion of the total metabolites. Two unidentified metabolites have also been found in the faeces. The pharmacological activity of the metabolites is not known. Hydroxylation of perhexiline is controlled by cytochrome P450 2D6 (CY P450 2D6).

SubstrateEnzymesProduct
Perhexiline
Not Available
cis-Hydroxy PerhexilineDetails
Perhexiline
Not Available
MonohydroxyperhexilineDetails
Route of eliminationNot Available
Half lifeVariable and non-linear. Some reports show a half-life of 2-6 days, others indicate it could be as high as 30 days.
ClearanceNot Available
ToxicityOral LD50 rat: 2150 mg/kg; Oral LD50 Mouse: 2641 mg/kg. Short term adverse effects include nausea, transient dizziness, hypoglycaemia in diabetic patients, and torsade de pointes (rare).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9818
Blood Brain Barrier+0.9796
Caco-2 permeable+0.6799
P-glycoprotein substrateNon-substrate0.5484
P-glycoprotein inhibitor INon-inhibitor0.8782
P-glycoprotein inhibitor IINon-inhibitor0.8888
Renal organic cation transporterInhibitor0.6665
CYP450 2C9 substrateNon-substrate0.8539
CYP450 2D6 substrateSubstrate0.8919
CYP450 3A4 substrateNon-substrate0.7558
CYP450 1A2 substrateInhibitor0.9107
CYP450 2C9 inhibitorNon-inhibitor0.9071
CYP450 2D6 inhibitorInhibitor0.8931
CYP450 2C19 inhibitorNon-inhibitor0.9025
CYP450 3A4 inhibitorNon-inhibitor0.8779
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.8452
Ames testNon AMES toxic0.9132
CarcinogenicityNon-carcinogens0.9548
BiodegradationNot ready biodegradable0.8346
Rat acute toxicity2.7630 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.7559
hERG inhibition (predictor II)Non-inhibitor0.6082
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397 )
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage formsNot Available
PricesNot Available
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
water solubility0.0608 mg/LNot Available
logP6.2Not Available
Predicted Properties
PropertyValueSource
Water Solubility2.72e-05 mg/mLALOGPS
logP5.87ALOGPS
logP5.53ChemAxon
logS-7ALOGPS
pKa (Strongest Basic)10.58ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 Å2ChemAxon
Rotatable Bond Count4ChemAxon
Refractivity87.23 m3·mol-1ChemAxon
Polarizability36.22 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
Spectra
Spectrum TypeDescriptionSplash Key
MSMass Spectrum (Electron Ionization)splash10-z200000000-e8335ba9964dd32ada29View in MoNA
References
Synthesis Reference

Stephen W. Horgan, Frank P. Palopoli, Edward J. Schwoegler, “Process for preparing 2-(2,2-dicyclohexylethyl)piperidine.” U.S. Patent US4069222, issued August, 1950.

US4069222
General ReferencesNot Available
External Links
ATC CodesC08EX02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSDownload (25.6 KB)
Interactions
Drug Interactions
Drug
AcetaminophenThe metabolism of Perhexiline can be increased when combined with Acetaminophen.
AmobarbitalThe metabolism of Perhexiline can be increased when combined with Amobarbital.
Atracurium besylatePerhexiline may increase the neuromuscular blocking activities of Atracurium besylate.
ButabarbitalThe metabolism of Perhexiline can be increased when combined with Butabarbital.
ButalbitalThe metabolism of Perhexiline can be increased when combined with Butalbital.
CaffeineThe metabolism of Perhexiline can be increased when combined with Caffeine.
Calcium AcetateThe therapeutic efficacy of Perhexiline can be decreased when used in combination with Calcium Acetate.
Calcium carbonateThe therapeutic efficacy of Perhexiline can be decreased when used in combination with Calcium carbonate.
Calcium ChlorideThe therapeutic efficacy of Perhexiline can be decreased when used in combination with Calcium Chloride.
Calcium citrateThe therapeutic efficacy of Perhexiline can be decreased when used in combination with Calcium citrate.
Calcium gluconateThe therapeutic efficacy of Perhexiline can be decreased when used in combination with Calcium gluconate.
CimetidineThe serum concentration of Perhexiline can be increased when it is combined with Cimetidine.
Cisatracurium besylatePerhexiline may increase the neuromuscular blocking activities of Cisatracurium besylate.
ClarithromycinThe metabolism of Perhexiline can be decreased when combined with Clarithromycin.
ClopidogrelThe therapeutic efficacy of Clopidogrel can be decreased when used in combination with Perhexiline.
DoxazosinDoxazosin may increase the hypotensive activities of Perhexiline.
EfavirenzThe serum concentration of Perhexiline can be decreased when it is combined with Efavirenz.
ErythromycinThe metabolism of Perhexiline can be decreased when combined with Erythromycin.
FluconazoleThe serum concentration of Perhexiline can be increased when it is combined with Fluconazole.
FosphenytoinThe serum concentration of Fosphenytoin can be increased when it is combined with Perhexiline.
ItraconazoleThe risk or severity of adverse effects can be increased when Itraconazole is combined with Perhexiline.
KetoconazoleThe risk or severity of adverse effects can be increased when Ketoconazole is combined with Perhexiline.
Magnesium chlorideThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium chloride.
Magnesium citrateThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium citrate.
Magnesium hydroxideThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium hydroxide.
Magnesium oxideThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium oxide.
Magnesium salicylateThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium salicylate.
Magnesium SulfateThe risk or severity of adverse effects can be increased when Perhexiline is combined with Magnesium Sulfate.
MethohexitalThe metabolism of Perhexiline can be increased when combined with Methohexital.
NafcillinThe metabolism of Perhexiline can be increased when combined with Nafcillin.
NitroprussidePerhexiline may increase the hypotensive activities of Nitroprusside.
PancuroniumPerhexiline may increase the neuromuscular blocking activities of Pancuronium.
PentobarbitalThe metabolism of Perhexiline can be increased when combined with Pentobarbital.
PhenobarbitalThe metabolism of Perhexiline can be increased when combined with Phenobarbital.
PhenoxybenzaminePhenoxybenzamine may increase the hypotensive activities of Perhexiline.
PhentolaminePhentolamine may increase the hypotensive activities of Perhexiline.
PhenytoinThe serum concentration of Phenytoin can be increased when it is combined with Perhexiline.
PosaconazoleThe risk or severity of adverse effects can be increased when Posaconazole is combined with Perhexiline.
PrazosinPrazosin may increase the hypotensive activities of Perhexiline.
RifabutinThe serum concentration of Perhexiline can be decreased when it is combined with Rifabutin.
RifampicinThe serum concentration of Perhexiline can be decreased when it is combined with Rifampicin.
RifapentineThe serum concentration of Perhexiline can be decreased when it is combined with Rifapentine.
RocuroniumPerhexiline may increase the neuromuscular blocking activities of Rocuronium.
SecobarbitalThe metabolism of Perhexiline can be increased when combined with Secobarbital.
SilodosinSilodosin may increase the hypotensive activities of Perhexiline.
SulfisoxazoleThe metabolism of Perhexiline can be decreased when combined with Sulfisoxazole.
TamsulosinTamsulosin may increase the hypotensive activities of Perhexiline.
TelithromycinThe metabolism of Perhexiline can be decreased when combined with Telithromycin.
TerazosinTerazosin may increase the hypotensive activities of Perhexiline.
VecuroniumPerhexiline may increase the neuromuscular blocking activities of Vecuronium.
VoriconazoleThe risk or severity of adverse effects can be increased when Voriconazole is combined with Perhexiline.
Food InteractionsNot Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Carnitine o-palmitoyltransferase activity
Specific Function:
Catalyzes the transfer of the acyl group of long-chain fatty acid-CoA conjugates onto carnitine, an essential step for the mitochondrial uptake of long-chain fatty acids and their subsequent beta-oxidation in the mitochondrion. Plays an important role in triglyceride metabolism.
Gene Name:
CPT1A
Uniprot ID:
P50416
Molecular Weight:
88366.92 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284 ]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423 ]
  3. Kennedy JA, Kiosoglous AJ, Murphy GA, Pelle MA, Horowitz JD: Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol. 2000 Dec;36(6):794-801. [PubMed:11117381 ]
  4. Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD: Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J Cardiovasc Pharmacol. 2005 Dec;46(6):849-55. [PubMed:16306812 ]
  5. Kennedy JA, Unger SA, Horowitz JD: Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol. 1996 Jul 26;52(2):273-80. [PubMed:8694852 ]
  6. Ashrafian H, Horowitz JD, Frenneaux MP: Perhexiline. Cardiovasc Drug Rev. 2007 Spring;25(1):76-97. [PubMed:17445089 ]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352 ]
Kind
Protein
Organism
Human
Pharmacological action
yes
Actions
inhibitor
General Function:
Carnitine o-palmitoyltransferase activity
Specific Function:
Not Available
Gene Name:
CPT2
Uniprot ID:
P23786
Molecular Weight:
73776.335 Da
References
  1. Kennedy JA, Kiosoglous AJ, Murphy GA, Pelle MA, Horowitz JD: Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol. 2000 Dec;36(6):794-801. [PubMed:11117381 ]
  2. Unger SA, Kennedy JA, McFadden-Lewis K, Minerds K, Murphy GA, Horowitz JD: Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium. J Cardiovasc Pharmacol. 2005 Dec;46(6):849-55. [PubMed:16306812 ]
  3. Kennedy JA, Unger SA, Horowitz JD: Inhibition of carnitine palmitoyltransferase-1 in rat heart and liver by perhexiline and amiodarone. Biochem Pharmacol. 1996 Jul 26;52(2):273-80. [PubMed:8694852 ]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrateinhibitor
General Function:
Steroid hydroxylase activity
Specific Function:
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.
Gene Name:
CYP2D6
Uniprot ID:
P10635
Molecular Weight:
55768.94 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
  2. Drug Interactions: Cytochrome P450 Drug Interaction Table [Link]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Steroid hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Acts as a 1,4-cineole 2-exo-monooxygenase.
Gene Name:
CYP2B6
Uniprot ID:
P20813
Molecular Weight:
56277.81 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Kind
Protein
Organism
Human
Pharmacological action
unknown
Actions
substrate
General Function:
Vitamin d3 25-hydroxylase activity
Specific Function:
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4-hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiot...
Gene Name:
CYP3A4
Uniprot ID:
P08684
Molecular Weight:
57342.67 Da
References
  1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
Comments
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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13