Perhexiline maleate | CAS#6724-53-4 | Antiangial agent

MedKoo Cat#: 318471 | Name: Perhexiline maleate

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Perhexiline is a prophylactic antianginal agent. Perhexiline is thought to act by inhibiting mitochondrial carnitine palmitoyltransferase-1. This shifts myocardial metabolism from fatty acid to glucose utilisation which results in increased ATP production for the same O2 consumption and consequently increases myocardial efficiency. Its clinical use has been limited by its narrow therapeutic index and high inter- and intra-individual pharmacokinetic variability.

Chemical Structure

Perhexiline maleate

CAS#6724-53-4 (maleate)

Theoretical Analysis

MedKoo Cat#: 318471

Name: Perhexiline maleate

CAS#: 6724-53-4 (maleate)

Chemical Formula: C23H39NO4

Exact Mass: 0.0000

Molecular Weight: 393.57

Elemental Analysis: C, 70.19; H, 9.99; N, 3.56; O, 16.26

Price and Availability

Size	Price	Availability
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,350.00	Ready to ship
500mg	USD 2,450.00	Ready to ship
1g	USD 3,850.00	Ready to ship
2g	USD 5,450.00	2 Weeks

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Related CAS #

6621-47-2 (free base) 6724-53-4 (maleate)

Synonym

Perhexiline maleate;

IUPAC/Chemical Name

2-(2,2-dicyclohexylethyl)piperidine maleate

InChi Key

JDZOTSLZMQDFLG-BTJKTKAUSA-N

InChi Code

InChI=1S/C19H35N.C4H4O4/c1-3-9-16(10-4-1)19(17-11-5-2-6-12-17)15-18-13-7-8-14-20-18;5-3(6)1-2-4(7)8/h16-20H,1-15H2;1-2H,(H,5,6)(H,7,8)/b;2-1-

SMILES Code

C1CCC(CC1)C(CC2CCCCN2)C3CCCCC3.C(=CC(=O)O)C(=O)O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO, not in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

It was outlawed in many countries due to its adverse effects on poor metabolisers (PM). The product has been reintroduced for patients who have contraindications, or have not responded to other treatments for angina.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#T24D04P22

QC Data

View QC data: current batch, Lot#T24D04P22

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Perhexiline maleate is an orally active CPT1 and CPT2 inhibitor.

In vitro activity:

In primary human hepatocytes, HepaRG cells, and HepG2 cells, perhexiline induced cell death in a concentration- and time-dependent manner. Perhexiline treatment also caused a significant increase in caspase 3/7 activity at 2 h and 4 h. Pretreatment with specific caspase inhibitors suggested that both intrinsic and extrinsic apoptotic pathways contributed to perhexiline-induced cytotoxicity, which was confirmed by increased expression of TNF-α, cleavage of caspase 3 and 9 upon perhexiline treatment. Moreover, perhexiline caused mitochondrial dysfunction, demonstrated by the classic glucose-galactose assay at 4 h and 24 h. Results from JC-1 staining suggested perhexiline caused loss of mitochondrial potential. Reference: Toxicol In Vitro. 2020 Dec;69:104987. https://pubmed.ncbi.nlm.nih.gov/32861758/

In vivo activity:

As shown in Figure 6a–6b, there was a significant decrease in leukemia cell counts in all mice after drug treatment (P<0.01). Importantly, flow cytometry analysis of the cell for expression of CD5 and IgM revealed that 59% of the cells were CD5+/IgM+ leukemia cells in the pre-treatment samples, whereas only 0.9% cells were CD5+/IgM+ after drug treatment (Figure 6c), indicating that the leukemia cell population (CD5+/IgM+ population) were selectively eliminated in vivo by Perhexiline, with most (99%) of the remaining cells were CD5/IgM negative cells. Reference: Oncogene. 2016 Oct 27;35(43):5663-5673. https://pubmed.ncbi.nlm.nih.gov/27065330/

	Solvent	mg/mL	mM
Solubility
	DMF	25.0	63.52
	DMSO	37.7	95.87
	DMSO:PBS (pH 7.2) (1:1)	0.5	1.27
	Ethanol	10.7	27.23

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 393.57 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Ren Z, Chen S, Seo JE, Guo X, Li D, Ning B, Guo L. Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol In Vitro. 2020 Dec;69:104987. doi: 10.1016/j.tiv.2020.104987. Epub 2020 Aug 28. PMID: 32861758; PMCID: PMC7938330. 2. 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. doi: 10.1016/0006-2952(96)00204-3. PMID: 8694852. 3. Kant S, Kesarwani P, Guastella AR, Kumar P, Graham SF, Buelow KL, Nakano I, Chinnaiyan P. Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma. Mol Cancer Ther. 2020 Jul;19(7):1415-1422. doi: 10.1158/1535-7163.MCT-19-1047. Epub 2020 May 19. PMID: 32430486; PMCID: PMC7335329. 4. Liu PP, Liu J, Jiang WQ, Carew JS, Ogasawara MA, Pelicano H, Croce CM, Estrov Z, Xu RH, Keating MJ, Huang P. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene. 2016 Oct 27;35(43):5663-5673. doi: 10.1038/onc.2016.103. Epub 2016 Apr 11. PMID: 27065330; PMCID: PMC5064824.

In vitro protocol:

In vivo protocol:

1. Kant S, Kesarwani P, Guastella AR, Kumar P, Graham SF, Buelow KL, Nakano I, Chinnaiyan P. Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma. Mol Cancer Ther. 2020 Jul;19(7):1415-1422. doi: 10.1158/1535-7163.MCT-19-1047. Epub 2020 May 19. PMID: 32430486; PMCID: PMC7335329. 2. Liu PP, Liu J, Jiang WQ, Carew JS, Ogasawara MA, Pelicano H, Croce CM, Estrov Z, Xu RH, Keating MJ, Huang P. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene. 2016 Oct 27;35(43):5663-5673. doi: 10.1038/onc.2016.103. Epub 2016 Apr 11. PMID: 27065330; PMCID: PMC5064824.

1: Jiang S, Fu W, Wang S, Zhu G, Wang J, Ma Y. Bacterial Outer Membrane Vesicles Loaded with Perhexiline Suppress Tumor Development by Regulating Tumor- Associated Macrophages Repolarization in a Synergistic Way. Int J Mol Sci. 2023 Jul 7;24(13):11222. doi: 10.3390/ijms241311222. PMID: 37446401; PMCID: PMC10342243. 2: Reyes-Castellanos G, Abdel Hadi N, Gallardo-Arriaga S, Masoud R, Garcia J, Lac S, El Kaoutari A, Gicquel T, Planque M, Fendt SM, Linares LK, Gayet O, Guillaumond F, Dusetti N, Iovanna J, Carrier A. Combining the antianginal drug perhexiline with chemotherapy induces complete pancreatic cancer regression in vivo. iScience. 2023 May 19;26(6):106899. doi: 10.1016/j.isci.2023.106899. PMID: 37305702; PMCID: PMC10250830. 3: Dhakal B, Tomita Y, Drew P, Price T, Maddern G, Smith E, Fenix K. Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects. Molecules. 2023 Apr 21;28(8):3624. doi: 10.3390/molecules28083624. PMID: 37110858; PMCID: PMC10145508. 4: Dhakal B, Li CMY, Ramezanpour M, Houtak G, Li R, Bouras G, Collela A, Chegeni N, Chataway TK, Drew P, Sallustio BC, Vreugde S, Smith E, Maddern G, Licari G, Fenix K. Proteomic characterisation of perhexiline treatment on THP-1 M1 macrophage differentiation. Front Immunol. 2023 Mar 13;14:1054588. doi: 10.3389/fimmu.2023.1054588. PMID: 36993962; PMCID: PMC10040681. 5: Chong CR, Liu S, Imam H, Heresztyn T, Sallustio BC, Chirkov YY, Horowitz JD. Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling. Biomedicines. 2022 Sep 23;10(10):2381. doi: 10.3390/biomedicines10102381. PMID: 36289640; PMCID: PMC9598312. 6: Ren Z, Chen S, Qin X, Li F, Guo L. Study of the roles of cytochrome P450 (CYPs) in the metabolism and cytotoxicity of perhexiline. Arch Toxicol. 2022 Dec;96(12):3219-3231. doi: 10.1007/s00204-022-03369-0. Epub 2022 Sep 9. PMID: 36083301; PMCID: PMC10395006. 7: Dhakal B, Li CMY, Li R, Yeo K, Wright JA, Gieniec KA, Vrbanac L, Sammour T, Lawrence M, Thomas M, Lewis M, Perry J, Worthley DL, Woods SL, Drew P, Sallustio BC, Smith E, Horowitz JD, Maddern GJ, Licari G, Fenix K. The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing. Cancers (Basel). 2022 Feb 18;14(4):1043. doi: 10.3390/cancers14041043. PMID: 35205791; PMCID: PMC8869789. 8: Midei MG, Darpo B, Ayers G, Brown R, Couderc JP, Daly W, Ferber G, Sager PT, Camm AJ. Electrophysiological and ECG Effects of Perhexiline, a Mixed Cardiac Ion Channel Inhibitor, Evaluated in Nonclinical Assays and in Healthy Subjects. J Clin Pharmacol. 2021 Dec;61(12):1606-1617. doi: 10.1002/jcph.1934. Epub 2021 Jul 20. PMID: 34214210. 9: Ananthakrishna R, Lee SL, Foote J, Sallustio BC, Binda G, Mangoni AA, Woodman R, Semsarian C, Horowitz JD, Selvanayagam JB. Randomized controlled trial of perhexiline on regression of left ventricular hypertrophy in patients with symptomatic hypertrophic cardiomyopathy (RESOLVE-HCM trial). Am Heart J. 2021 Oct;240:101-113. doi: 10.1016/j.ahj.2021.06.010. Epub 2021 Jun 25. PMID: 34175315. 10: Pfeffer TJ, List M, Müller JH, Scherr M, Bauersachs J, Hilfiker-Kleiner D, Ricke-Hoch M. Perhexiline treatment improves toxic effects of β-adrenergic receptor stimulation in experimental peripartum cardiomyopathy. ESC Heart Fail. 2021 Aug;8(4):3375-3381. doi: 10.1002/ehf2.13412. Epub 2021 May 17. PMID: 34002539; PMCID: PMC8318439. 11: Tan Y, Sia P, Simon S. Optic neuropathy secondary to perhexiline and amiodarone. BMJ Case Rep. 2021 Jan 27;14(1):e237727. doi: 10.1136/bcr-2020-237727. PMID: 33504523; PMCID: PMC7843302. 12: Ren Z, Chen S, Pak S, Guo L. A mechanism of perhexiline's cytotoxicity in hepatic cells involves endoplasmic reticulum stress and p38 signaling pathway. Chem Biol Interact. 2021 Jan 25;334:109353. doi: 10.1016/j.cbi.2020.109353. Epub 2020 Dec 9. PMID: 33309543; PMCID: PMC7982969. 13: Ren Z, Chen S, Seo JE, Guo X, Li D, Ning B, Guo L. Mitochondrial dysfunction and apoptosis underlie the hepatotoxicity of perhexiline. Toxicol In Vitro. 2020 Dec;69:104987. doi: 10.1016/j.tiv.2020.104987. Epub 2020 Aug 28. PMID: 32861758; PMCID: PMC7938330. 14: Guidi A, Prasanth Saraswati A, Relitti N, Gimmelli R, Saccoccia F, Sirignano C, Taglialatela-Scafati O, Campiani G, Ruberti G, Gemma S. (+)-(R)- and (-)-(S)-Perhexiline maleate: Enantioselective synthesis and functional studies on Schistosoma mansoni larval and adult stages. Bioorg Chem. 2020 Sep;102:104067. doi: 10.1016/j.bioorg.2020.104067. Epub 2020 Jun 30. PMID: 32663671. 15: Kant S, Kesarwani P, Guastella AR, Kumar P, Graham SF, Buelow KL, Nakano I, Chinnaiyan P. Perhexiline Demonstrates FYN-mediated Antitumor Activity in Glioblastoma. Mol Cancer Ther. 2020 Jul;19(7):1415-1422. doi: 10.1158/1535-7163.MCT-19-1047. Epub 2020 May 19. PMID: 32430486; PMCID: PMC7335329. 16: Licari G, Milne RW, Somogyi AA, Sallustio BC. Enantioselectivity in the tissue distribution of perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats. Pharmacol Res Perspect. 2018 Jun;6(3):e00406. doi: 10.1002/prp2.406. Epub 2018 May 22. PMID: 29864243; PMCID: PMC5980244. 17: Camilleri P, Zhang D, Midei M, Daly W, Copp J, Flinn C, Luongo C, Shamszad P. The validation of an LC-MS/MS assay for perhexiline and major hydroxy metabolites, and its application to therapeutic monitoring in patient plasma. Bioanalysis. 2017 Jul;9(13):1011-1025. doi: 10.4155/bio-2017-0068. Epub 2017 Jul 10. PMID: 28692346. 18: Tseng CC, Noordali H, Sani M, Madhani M, Grant DM, Frenneaux MP, Zanda M, Greig IR. Development of Fluorinated Analogues of Perhexiline with Improved Pharmacokinetic Properties and Retained Efficacy. J Med Chem. 2017 Apr 13;60(7):2780-2789. doi: 10.1021/acs.jmedchem.6b01592. Epub 2017 Mar 21. PMID: 28277663. 19: Liu PP, Liu J, Jiang WQ, Carew JS, Ogasawara MA, Pelicano H, Croce CM, Estrov Z, Xu RH, Keating MJ, Huang P. Elimination of chronic lymphocytic leukemia cells in stromal microenvironment by targeting CPT with an antiangina drug perhexiline. Oncogene. 2016 Oct 27;35(43):5663-5673. doi: 10.1038/onc.2016.103. Epub 2016 Apr 11. PMID: 27065330; PMCID: PMC5064824. 20: Guidi A, Lalli C, Perlas E, Bolasco G, Nibbio M, Monteagudo E, Bresciani A, Ruberti G. Discovery and Characterization of Novel Anti-schistosomal Properties of the Anti-anginal Drug, Perhexiline and Its Impact on Schistosoma mansoni Male and Female Reproductive Systems. PLoS Negl Trop Dis. 2016 Aug 12;10(8):e0004928. doi: 10.1371/journal.pntd.0004928. PMID: 27518281; PMCID: PMC4982595.