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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
SynonymLanguageCode
(-)-2-(2,2-Dicyclohexylethyl)piperidineNot AvailableNot Available
(+)-2-(2,2-Dicyclohexylethyl)piperidineNot AvailableNot Available
2-(2,2-Dicyclohexylethyl)piperidineNot AvailableNot Available
PerhexileneNot AvailableNot Available
PerhexilinaSpanishINN
PerhexilineNot AvailableNot Available
PerhexilinumLatinINN
PerhexillineNot AvailableNot Available
SaltsNot Available
Brand namesNot Available
Brand mixturesNot Available
Categories
CAS number6621-47-2
WeightAverage: 277.4879
Monoisotopic: 277.276950125
Chemical FormulaC19H35N
InChI KeyCYXKNKQEMFBLER-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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassAlkaloids and Derivatives
ClassNot Available
SubclassNot Available
Direct parentAlkaloids and Derivatives
Alternative parentsPiperidines; Polyamines; Dialkylamines
Substituentspiperidine; secondary amine; secondary aliphatic amine; polyamine; amine; organonitrogen compound
Classification descriptionThis compound belongs to the alkaloids and derivatives. These are naturally occurring chemical compounds that contain mostly basic nitrogen atoms. This group also includes some related compounds with neutral and even weakly acidic properties. Also some synthetic compounds of similar structure are attributed to alkaloids. In addition to carbon, hydrogen and nitrogen, alkaloids may also contain oxygen, sulfur and more rarely other elements such as chlorine, bromine, and phosphorus.
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.
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
Property Value Probability
Human Intestinal Absorption + 0.9818
Blood Brain Barrier + 0.9796
Caco-2 permeable + 0.6799
P-glycoprotein substrate Non-substrate 0.5484
P-glycoprotein inhibitor I Non-inhibitor 0.8782
P-glycoprotein inhibitor II Non-inhibitor 0.8888
Renal organic cation transporter Inhibitor 0.6665
CYP450 2C9 substrate Non-substrate 0.8539
CYP450 2D6 substrate Substrate 0.8919
CYP450 3A4 substrate Non-substrate 0.7558
CYP450 1A2 substrate Inhibitor 0.9107
CYP450 2C9 substrate Non-inhibitor 0.9071
CYP450 2D6 substrate Inhibitor 0.8931
CYP450 2C19 substrate Non-inhibitor 0.9025
CYP450 3A4 substrate Non-inhibitor 0.8779
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.8452
Ames test Non AMES toxic 0.9132
Carcinogenicity Non-carcinogens 0.9548
Biodegradation Not ready biodegradable 0.8346
Rat acute toxicity 2.7630 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.7559
hERG inhibition (predictor II) Non-inhibitor 0.6082
Pharmacoeconomics
ManufacturersNot Available
PackagersNot Available
Dosage forms
FormRouteStrength
TabletOral
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 g/lALOGPS
logP5.87ALOGPS
logP5.53ChemAxon
logS-7ALOGPS
pKa (strongest basic)10.58ChemAxon
physiological charge1ChemAxon
hydrogen acceptor count1ChemAxon
hydrogen donor count1ChemAxon
polar surface area12.03ChemAxon
rotatable bond count4ChemAxon
refractivity87.23ChemAxon
polarizability36.22ChemAxon
number of rings3ChemAxon
bioavailability1ChemAxon
rule of fiveNoChemAxon
Ghose filterYesChemAxon
Veber's ruleYesChemAxon
MDDR-like ruleNoChemAxon
Spectra
SpectraNot Available
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 ReferenceNot Available
External Links
ResourceLink
PubChem Compound4746
PubChem Substance46504471
ChemSpider4584
ChEBI35553
ChEMBLCHEMBL75880
Therapeutic Targets DatabaseDAP000957
PharmGKBPA130150436
WikipediaPerhexiline
ATC CodesC08EX02
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelNot Available
MSDSshow(25.6 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Carnitine O-palmitoyltransferase 1, liver isoform

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carnitine O-palmitoyltransferase 1, liver isoform P50416 Details

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
  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
  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
  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
  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
  6. Ashrafian H, Horowitz JD, Frenneaux MP: Perhexiline. Cardiovasc Drug Rev. 2007 Spring;25(1):76-97. Pubmed
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. Carnitine O-palmitoyltransferase 2, mitochondrial

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Carnitine O-palmitoyltransferase 2, mitochondrial P23786 Details

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
  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
  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

Enzymes

1. Cytochrome P450 2D6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 2D6 P10635 Details

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

2. Cytochrome P450 2B6

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 2B6 P20813 Details

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. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

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. Epub 2009 Nov 24. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:13