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Record Information
Version2.0
Creation Date2009-07-21 20:28:18 UTC
Update Date2014-12-24 20:25:54 UTC
Accession NumberT3D2975
Identification
Common NamePerhexiline
ClassSmall Molecule
DescriptionPerhexiline is only found in individuals that have used or taken this drug. It is a coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis. [PubChem]Perhexiline 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.
Compound Type
  • Amine
  • Calcium Channel Blocker
  • Cardiovascular Agent
  • Drug
  • Metabolite
  • Organic Compound
  • Synthetic Compound
  • Vasodilator Agent
Chemical Structure
Thumb
Synonyms
Synonym
(+)-2-(2,2-Dicyclohexylethyl)piperidine
(-)-2-(2,2-Dicyclohexylethyl)piperidine
2-(2,2-Dicyclohexylethyl)piperidine
Perhexilene
Perhexilina
Perhexilinum
Perhexilline
Chemical FormulaC19H35N
Average Molecular Mass277.488 g/mol
Monoisotopic Mass277.277 g/mol
CAS Registry Number6621-47-2
IUPAC Name2-(2,2-dicyclohexylethyl)piperidine
Traditional Nameperhexiline
SMILESC(C(C1CCCCC1)C1CCCCC1)C1CCCCN1
InChI IdentifierInChI=1/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
InChI KeyInChIKey=CYXKNKQEMFBLER-UHFFFAOYNA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as piperidines. Piperidines 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
  • Organic nitrogen compound
  • Organopnictogen compound
  • Hydrocarbon derivative
  • Organonitrogen compound
  • Amine
  • Aliphatic heteromonocyclic compound
Molecular FrameworkAliphatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Cytoplasm
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
Solubility0.0608 mg/L
LogP6.2
Predicted Properties
PropertyValueSource
Water Solubility2.7e-05 g/LALOGPS
logP5.87ALOGPS
logP5.53ChemAxon
logS-7ALOGPS
pKa (Strongest Basic)10.58ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area12.03 ŲChemAxon
Rotatable Bond Count4ChemAxon
Refractivity87.23 m³·mol⁻¹ChemAxon
Polarizability36.22 ųChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-001i-9240000000-7d469dd2b3d8bdb97f5c2017-09-01View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot Available2021-10-12View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-004i-1090000000-f6b8ccc29365a1b9553f2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-057i-4190000000-e00b24bda85621e908942016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-052f-5290000000-6389e823b74d83649abe2016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0090000000-956a531f36ba4bf827192016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0090000000-6374e56bfc2eb86097942016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-001i-9170000000-3d144881a6a7aec9d1112016-08-03View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-004i-0090000000-745fd042a988e5d1440b2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-004i-2190000000-9d556eceea83c2bc40212021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-000t-9200000000-2793cdd7988a27b7095e2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-004i-0090000000-f4712ee2d57b7f19751d2021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-004i-0090000000-4b2ad669814aa4255d882021-10-11View Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-00di-0090000000-8d81ed304a7cf5c905ea2021-10-11View Spectrum
MSMass Spectrum (Electron Ionization)splash10-001i-9000000000-e8335ba9964dd32ada292014-09-20View Spectrum
Toxicity Profile
Route of ExposureWell absorbed (>80%) from the gastrointestinal tract following oral administration.
Mechanism of ToxicityPerhexiline 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.
MetabolismThe 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). Half Life: Variable and non-linear. Some reports show a half-life of 2-6 days, others indicate it could be as high as 30 days.
Toxicity ValuesLD50: 2150 mg/kg (Oral, Rat) (1) LD50: 2641 mg/kg (Oral, Mouse) (1)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor the management of severe angina pectoris.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsShort term adverse effects include nausea, transient dizziness, hypoglycaemia in diabetic patients, and torsade de pointes (rare).
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB01074
HMDB IDHMDB15207
PubChem Compound ID4746
ChEMBL IDCHEMBL75880
ChemSpider ID4584
KEGG IDNot Available
UniProt IDNot Available
OMIM ID
ChEBI ID35553
BioCyc IDNot Available
CTD IDNot Available
Stitch IDPerhexiline
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkPerhexiline
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.

MSDSLink
General References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
Gene Regulation
Up-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails
Down-Regulated Genes
GeneGene SymbolGene IDInteractionChromosomeDetails

Targets

General Function:
Voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization
Specific Function:
Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. Channel properties are modulated by cAMP and subunit assembly. Mediates the rapidly activating component of the delayed rectifying potassium current in heart (IKr). Isoforms USO have no channel activity by themself, but modulates channel characteristics by forming heterotetramers with other isoforms which are retained intracellularly and undergo ubiquitin-dependent degradation.
Gene Name:
KCNH2
Uniprot ID:
Q12809
Molecular Weight:
126653.52 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC507.8 uMNot AvailableBindingDB 50117921
IC507.762 uMNot AvailableBindingDB 50117921
IC507.76247 uMNot AvailableBindingDB 50117921
References
  1. Keseru GM: Prediction of hERG potassium channel affinity by traditional and hologram qSAR methods. Bioorg Med Chem Lett. 2003 Aug 18;13(16):2773-5. [12873512 ]
  2. Rajamani R, Tounge BA, Li J, Reynolds CH: A two-state homology model of the hERG K+ channel: application to ligand binding. Bioorg Med Chem Lett. 2005 Mar 15;15(6):1737-41. [15745831 ]
  3. Jia L, Sun H: Support vector machines classification of hERG liabilities based on atom types. Bioorg Med Chem. 2008 Jun 1;16(11):6252-60. doi: 10.1016/j.bmc.2008.04.028. Epub 2008 Apr 16. [18448342 ]
  4. Ermondi G, Visentin S, Caron G: GRIND-based 3D-QSAR and CoMFA to investigate topics dominated by hydrophobic interactions: the case of hERG K+ channel blockers. Eur J Med Chem. 2009 May;44(5):1926-32. doi: 10.1016/j.ejmech.2008.11.009. Epub 2008 Nov 28. [19110341 ]
  5. Cavalli A, Poluzzi E, De Ponti F, Recanatini M: Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers. J Med Chem. 2002 Aug 29;45(18):3844-53. [12190308 ]
  6. Perrin MJ, Kuchel PW, Campbell TJ, Vandenberg JI: Drug binding to the inactivated state is necessary but not sufficient for high-affinity binding to human ether-a-go-go-related gene channels. Mol Pharmacol. 2008 Nov;74(5):1443-52. doi: 10.1124/mol.108.049056. Epub 2008 Aug 13. [18701618 ]
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
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>100 uMNot AvailableBindingDB 50117921
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Ceccarelli SM, Chomienne O, Gubler M, Arduini A: Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011 May 12;54(9):3109-52. doi: 10.1021/jm100809g. Epub 2011 Apr 19. [21504156 ]
General Function:
Carnitine o-palmitoyltransferase activity
Specific Function:
Not Available
Gene Name:
CPT2
Uniprot ID:
P23786
Molecular Weight:
73776.335 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5072.8 uMNot AvailableBindingDB 50117921
References
  1. Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. [18048412 ]
  2. Ceccarelli SM, Chomienne O, Gubler M, Arduini A: Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011 May 12;54(9):3109-52. doi: 10.1021/jm100809g. Epub 2011 Apr 19. [21504156 ]
General Function:
Carnitine o-palmitoyltransferase activity
Specific Function:
Not Available
Gene Name:
CPT1B
Uniprot ID:
Q92523
Molecular Weight:
87800.385 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC50>100 uMNot AvailableBindingDB 50117921
References
  1. Ceccarelli SM, Chomienne O, Gubler M, Arduini A: Carnitine palmitoyltransferase (CPT) modulators: a medicinal chemistry perspective on 35 years of research. J Med Chem. 2011 May 12;54(9):3109-52. doi: 10.1021/jm100809g. Epub 2011 Apr 19. [21504156 ]