PERHEXILINE

Details

Stereochemistry	RACEMIC
Molecular Formula	C19H35N
Molecular Weight	277.4886
Optical Activity	( + / - )
Defined Stereocenters	0 / 1
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

C1CCC(CC1)C(CC2CCCCN2)C3CCCCC3

InChI

InChIKey=CYXKNKQEMFBLER-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Molecular Formula	C19H35N
Molecular Weight	277.4886
Charge	0
Count

Stereochemistry	RACEMIC
Additional Stereochemistry	No
Defined Stereocenters	0 / 1
E/Z Centers	0
Optical Activity	( + / - )

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/17445089 | http://www.medsafe.govt.nz/profs/Datasheet/p/pexsigtab.pdf | http://adisinsight.springer.com/drugs/800037277

Perhexiline, 2-(2,2-dicyclohexylethyl)piperidine, is an anti-anginal drug. Perhexiline reduces fatty acid metabolism through the inhibition of carnitine palmitoyltransferase, the enzyme responsible for mitochondrial uptake of long-chain fatty acids. Perhexiline is used for reducing the frequency of moderate to severe attacks of angina pectoris due to coronary artery disease in patients who have not responded to other conventional therapy or in whom such therapy may be contraindicated. Heart Metabolics Limited is developing perhexiline for the treatment of hypertrophic cardiomyopathy

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Carnitine palmitoyltransferase 1A 5 Target ID: CHEMBL3858 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8694852	Inhibitor 7728	77.0 µM [IC50]
Carnitine palmitoyltransferase 1B 5 Target ID: CHEMBL3216 Sources: https://www.ncbi.nlm.nih.gov/pubmed/8694852	Inhibitor 7728	148.0 µM [IC50]
HERG 89 Target ID: CHEMBL240 Sources: https://www.ncbi.nlm.nih.gov/pubmed/10369479 \| https://www.ncbi.nlm.nih.gov/pubmed/18701618	Blocker 511	7.8 µM [IC50]
Voltage-gated potassium channel subunit Kv1.5 36 Target ID: CHEMBL4306 Sources: https://www.ncbi.nlm.nih.gov/pubmed/7616429	Blocker 511	1.5 µM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Angina pectoris 88 Sources: https://www.ncbi.nlm.nih.gov/pubmed/17445089	Primary	Approved 8043	PEXSIG Approved Use To reduce the frequency of moderate to severe attacks of angina pectoris due to coronary artery disease in patients who have not responded to other conventional therapy or in whom such therapy may be contraindicated. Launch Date 2.52374401E11
Hypertrophic cardiomyopathy 8 Sources: https://www.ncbi.nlm.nih.gov/pubmed/20921436	Primary	Phase II 1101	Unknown Approved Use Unknown
Schistosomiasis 32 Sources: https://www.ncbi.nlm.nih.gov/pubmed/27518281	Primary	Preclinical	Unknown Approved Use Unknown

PubMed

Title	Date	PubMed
[Electrophysiological study of latent neuropathies induced by perhexiline].	1978 Nov	81769
[The classic anti-anginal agents and molsidomine].	1983 Feb	6407452
Perhexilene neuropathy: a report of two cases.	1984 Jun	6093756
Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies.	1985 Sep-Oct	4029887
Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease.	2001	14728034
[Amphiphilic cationic drug myopathy, drug-induced lysosomal storage lipidosis].	2001	11596386
New tricks for an old drug.	2002 Dec	12473251
Leustroducsin B activates nuclear factor-kappaB via the acidic sphingomyelinase pathway in human bone marrow-derived stromal cell line KM-102.	2002 Mar	12034042
Correlation of CYP2D6 genotype with perhexiline phenotypic metabolizer status.	2003 Oct	14515061
Metabolic manipulation in ischaemic heart disease, a novel approach to treatment.	2004 Apr	15084367
Design, synthesis, and biological evaluation of novel T-Type calcium channel antagonists.	2004 Jul 16	15203145
Determination of perhexiline and hydroxyperhexiline in plasma by liquid chromatography-mass spectrometry.	2004 Jun 5	15113543
Dissociation between metabolic and efficiency effects of perhexiline in normoxic rat myocardium.	2005 Dec	16306812
Influence of different calcic antagonists on the Caco-2 cell monolayer integrity or "TEER, a measurement of toxicity?".	2005 Jan-Jun	16010866
Individualized drug and dose: the clinical pharmacologist's calling or curse?	2005 Nov	16405455
Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment.	2005 Nov 22	16301359
The influence of CYP2D6 genotype on trough plasma perhexiline and cis-OH-perhexiline concentrations following a standard loading regimen in patients with myocardial ischaemia.	2006 Mar	16487226
Determination of the 4-monohydroxy metabolites of perhexiline in human plasma, urine and liver microsomes by liquid chromatography.	2006 Nov 7	16837252
Can pharmacogenetics help rescue drugs withdrawn from the market?	2006 Sep	16981848
CYP2B6, CYP2D6, and CYP3A4 catalyze the primary oxidative metabolism of perhexiline enantiomers by human liver microsomes.	2007 Jan	17050648
Acidic extracellular pH increases calcium influx-triggered phospholipase D activity along with acidic sphingomyelinase activation to induce matrix metalloproteinase-9 expression in mouse metastatic melanoma.	2007 Jun	17540003
Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier?	2007 Nov	17765975
Perhexiline.	2007 Spring	17445089
Modulation of cardiac metabolism during myocardial ischemia.	2008	18991673
Pharmacologic profiling of human and rat cytochrome P450 1A1 and 1A2 induction and competition.	2008 Dec	18493746
Phospholipidosis assay in HepG2 cells and rat or rhesus hepatocytes using phospholipid probe NBD-PE.	2008 Jun	18537465
Gene expression profiling in rat liver treated with compounds inducing phospholipidosis.	2008 Jun 15	18355885
Metabolic agents in the management of diabetic coronary patients: a new era.	2008 Jun 23	18199501
Metabolic agents in the management of diabetic coronary patients: a new era.	2008 Jun 23	17561287
Steady-state pharmacokinetics of the enantiomers of perhexiline in CYP2D6 poor and extensive metabolizers administered Rac-perhexiline.	2008 Mar	17875193
Steatohepatitis-inducing drugs trigger cytokeratin cross-links in hepatocytes. Possible contribution to Mallory-Denk body formation.	2008 Sep	18603402
Ca2+-dependent functions in peptidoglycan-stimulated mouse dendritic cells.	2009	19710531
Effects of metabolic approach in diabetic patients with coronary artery disease.	2009	19275650
Agents with inotropic properties for the management of acute heart failure syndromes. Traditional agents and beyond.	2009 Dec	19876734
Prediction of pharmacological and xenobiotic responses to drugs based on time course gene expression profiles.	2009 Dec 2	19956587
Diabetic cardiomyopathy.	2009 May	19364331
Relationship between in vitro phospholipidosis assay using HepG2 cells and 2-week toxicity studies in rats.	2009 Oct	19793005
The adrenergic-fatty acid load in heart failure.	2009 Oct 27	19850204
Screen for chemical modulators of autophagy reveals novel therapeutic inhibitors of mTORC1 signaling.	2009 Sep 22	19771169
Stereoselective Inhibition of the hERG1 Potassium Channel.	2010	21833176
A novel screen using the Reck tumor suppressor gene promoter detects both conventional and metastasis-suppressing anticancer drugs.	2010 Aug	21304177
Niclosamide prevents the formation of large ubiquitin-containing aggregates caused by proteasome inhibition.	2010 Dec 23	21203451
Modulation of myocardial metabolism: an emerging therapeutic principle.	2010 Jul	20535068
Metabolic Fingerprinting in Toxicological Assessment Using FT-ICR MS.	2010 Jun	22272014
Effects of perhexiline on myocardial deformation in patients with ischaemic left ventricular dysfunction.	2010 Mar 4	19840889
Glucagon-like peptide-1 and the exenatide analogue AC3174 improve cardiac function, cardiac remodeling, and survival in rats with chronic heart failure.	2010 Nov 16	21080957
Perhexiline and hypertrophic cardiomyopathy: a new horizon for metabolic modulation.	2010 Oct 19	20921436
Profiling of a prescription drug library for potential renal drug-drug interactions mediated by the organic cation transporter 2.	2011 Jul 14	21599003
Comparison of a genomic and a multiplex cell imaging approach for the detection of phospholipidosis.	2011 Oct	21515356
A repurposing approach identifies off-patent drugs with fungicidal cryptococcal activity, a common structural chemotype, and pharmacological properties relevant to the treatment of cryptococcosis.	2013 Feb	23243064

Patents

Sample Use Guides

In Vivo Use Guide

Commence therapy with 100mg daily. Adjust progressively, up or down, at 2 to 4 weekly intervals based on the results of plasma level monitoring. It is generally advised not to administer more than 300mg per day, in divided doses, but in certain cases it may be necessary to use 400mg per day. The maintenance dose must be the minimum dose that is effective and well tolerated.

Route of Administration: Oral

In Vitro Use Guide

Perhexiline maleate was more potent on basal LH release from rat anterior pituitary cell aggregates than on LH stimulated by LHRH. The increases of basal LH secretion induced by perhexiline maleate were 69% (p < 0.001) at a concentration of 10(-7)M, 130% (p < 0.001) at a concentration of 10(-5)M and 250% (p < 0.001) at a concentration of 10(-4)M. Perhexiline maleate also increased the LHRH-stimulated LH release by 25.5% (p < 0.05) at a concentration of 10(-5)M and by 74.5% (p < 0.01) at the concentration of 10(-4)M.

Substance Class	Chemical Created by `admin` on `Sat Jun 26 14:35:09 UTC 2021` Edited by `admin` on `Sat Jun 26 14:35:09 UTC 2021`
Record UNII	KU65374X44
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

PERHEXILINE

Official Name

English

2-(2,2-DICYCLOHEXYLETHYL)PIPERIDINE

Systematic Name

English

PERHEXILINE [WHO-DD]

Common Name

English

(+/-)-2-(2,2-DICYCLOHEXYLETHYL)PIPERIDINE

Systematic Name

English

PERHEXILINE [INN]

Common Name

English

PERHEXILINE [MI]

Common Name

English

PIPERIDINE, 2-(2,2-DICYCLOHEXYLETHYL)-

Systematic Name

English

Classification Tree Code System Code

WHO-ATC

C08EX02