Perhexiline

Identification

Generic Name
Perhexiline
DrugBank Accession Number
DB01074
Background

Perhexiline is a coronary vasodilator used especially for angina of effort. It may cause neuropathy and hepatitis.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Weight
Average: 277.4879
Monoisotopic: 277.276950125
Chemical Formula
C19H35N
Synonyms
  • Perhexilene
  • Perhexilina
  • Perhexiline
  • Perhexilinum

Pharmacology

Indication

For the management of severe angina pectoris.

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Contraindications & Blackbox Warnings
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Pharmacodynamics

Used 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 action

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.

TargetActionsOrganism
ACarnitine O-palmitoyltransferase 1, liver isoform
inhibitor
Humans
ACarnitine O-palmitoyltransferase 2, mitochondrial
inhibitor
Humans
UPotassium voltage-gated channel subfamily H member 2Not AvailableHumans
Absorption

Well absorbed (>80%) from the gastrointestinal tract following oral administration.

Volume of distribution

Not Available

Protein binding

Perhexiline 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).

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Route of elimination

Not Available

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.

Clearance

Not Available

Adverse Effects
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Toxicity

Oral 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).

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Perhexiline can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Perhexiline can be increased when combined with Abatacept.
AbirateroneThe metabolism of Perhexiline can be decreased when combined with Abiraterone.
AcarboseThe risk or severity of hypoglycemia can be increased when Perhexiline is combined with Acarbose.
AcebutololPerhexiline may increase the arrhythmogenic activities of Acebutolol.
Food Interactions
Not Available

Products

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Product Ingredients
IngredientUNIICASInChI Key
Perhexiline maleateK7V8Y90G0H6724-53-4JDZOTSLZMQDFLG-UHFFFAOYSA-N

Categories

ATC Codes
C08EX02 — Perhexiline
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This 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.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Piperidines
Sub Class
Not Available
Direct Parent
Piperidines
Alternative Parents
Dialkylamines / Azacyclic compounds / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
Aliphatic heteromonocyclic compound / Amine / Azacycle / Hydrocarbon derivative / Organic nitrogen compound / Organonitrogen compound / Organopnictogen compound / Piperidine / Secondary aliphatic amine / Secondary amine
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
piperidines (CHEBI:35553)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
KU65374X44
CAS number
6621-47-2
InChI Key
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

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 References
Not Available
Human Metabolome Database
HMDB0015207
PubChem Compound
4746
PubChem Substance
46504471
ChemSpider
4584
BindingDB
61402
RxNav
8050
ChEBI
35553
ChEMBL
CHEMBL75880
Therapeutic Targets Database
DAP000957
PharmGKB
PA130150436
Wikipedia
Perhexiline
MSDS
Download (25.6 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3WithdrawnTreatmentHypertrophic Cardiomyopathy (HCM)1
2CompletedTreatmentChronic Heart Failure (CHF)1
2CompletedTreatmentHeart Failure, Diastolic1
2RecruitingTreatmentHypertrophic Cardiomyopathy (HCM)1
2TerminatedTreatmentFamilial Hypertrophic Cardiomyopathy / Hypertrophic Cardiomyopathy (HCM)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
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
Polarizability36.21 Å3Chemaxon
Number of Rings3Chemaxon
Bioavailability1Chemaxon
Rule of FiveNoChemaxon
Ghose FilterYesChemaxon
Veber's RuleYesChemaxon
MDDR-like RuleNoChemaxon
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)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSsplash10-001i-9240000000-7d469dd2b3d8bdb97f5c
Mass Spectrum (Electron Ionization)MSsplash10-001i-9000000000-e8335ba9964dd32ada29
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-0090000000-57ddc7d3a858d8997b3c
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0090000000-6bcc81c111feaed34b87
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-004i-2390000000-8fc06b799134c289e413
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-004i-0090000000-fa3e854ec65823680256
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0a5a-9640000000-5307857793a7cf9d1178
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-005a-3590000000-88b02ff0339e99949dc5
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
AdductCCS Value (Å2)Source typeSource
[M-H]-178.2902098
predicted
DarkChem Lite v0.1.0
[M-H]-165.67549
predicted
DeepCCS 1.0 (2019)
[M+H]+178.1033098
predicted
DarkChem Lite v0.1.0
[M+H]+168.0335
predicted
DeepCCS 1.0 (2019)
[M+Na]+178.4953098
predicted
DarkChem Lite v0.1.0
[M+Na]+174.12663
predicted
DeepCCS 1.0 (2019)

Targets

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insights and accelerate drug research.
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Kind
Protein
Organism
Humans
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-o...
Gene Name
CPT1A
Uniprot ID
P50416
Uniprot Name
Carnitine O-palmitoyltransferase 1, liver isoform
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  6. Ashrafian H, Horowitz JD, Frenneaux MP: Perhexiline. Cardiovasc Drug Rev. 2007 Spring;25(1):76-97. [Article]
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Carnitine o-palmitoyltransferase activity
Specific Function
Not Available
Gene Name
CPT2
Uniprot ID
P23786
Uniprot Name
Carnitine O-palmitoyltransferase 2, mitochondrial
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. [Article]
  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. [Article]
  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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
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 ...
Gene Name
KCNH2
Uniprot ID
Q12809
Uniprot Name
Potassium voltage-gated channel subfamily H member 2
Molecular Weight
126653.52 Da
References
  1. 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. [Article]

Enzymes

Kind
Protein
Organism
Humans
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 un...
Gene Name
CYP2B6
Uniprot ID
P20813
Uniprot Name
Cytochrome P450 2B6
Molecular Weight
56277.81 Da
References
  1. Davies BJ, Coller JK, Somogyi AA, Milne RW, Sallustio BC: CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes. Drug Metab Dispos. 2007 Jan;35(1):128-38. doi: 10.1124/dmd.106.012252. Epub 2006 Oct 18. [Article]
Kind
Protein
Organism
Humans
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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Davies BJ, Coller JK, Somogyi AA, Milne RW, Sallustio BC: CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes. Drug Metab Dispos. 2007 Jan;35(1):128-38. doi: 10.1124/dmd.106.012252. Epub 2006 Oct 18. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
Inhibitor
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...
Gene Name
CYP2D6
Uniprot ID
P10635
Uniprot Name
Cytochrome P450 2D6
Molecular Weight
55768.94 Da
References
  1. Davies BJ, Coller JK, Somogyi AA, Milne RW, Sallustio BC: CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes. Drug Metab Dispos. 2007 Jan;35(1):128-38. doi: 10.1124/dmd.106.012252. Epub 2006 Oct 18. [Article]
  2. Davies BJ, Coller JK, James HM, Gillis D, Somogyi AA, Horowitz JD, Morris RG, Sallustio BC: Clinical inhibition of CYP2D6-catalysed metabolism by the antianginal agent perhexiline. Br J Clin Pharmacol. 2004 Apr;57(4):456-63. doi: 10.1046/j.1365-2125.2003.02033.x. [Article]
  3. Flockhart Table of Drug Interactions [Link]

Drug created at June 13, 2005 13:24 / Updated at April 07, 2023 13:17