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Etomoxir

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Etomoxir
Names
IUPAC name
rac-Ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.225.462 Edit this at Wikidata
UNII
  • InChI=1S/C17H23ClO4/c1-2-20-16(19)17(13-22-17)11-5-3-4-6-12-21-15-9-7-14(18)8-10-15/h7-10H,2-6,11-13H2,1H3/t17-/m1/s1
    Key: DZLOHEOHWICNIL-QGZVFWFLSA-N
  • InChI=1/C17H23ClO4/c1-2-20-16(19)17(13-22-17)11-5-3-4-6-12-21-15-9-7-14(18)8-10-15/h7-10H,2-6,11-13H2,1H3/t17-/m1/s1
    Key: DZLOHEOHWICNIL-QGZVFWFLBM
  • CCOC(=O)[C@]1(CO1)CCCCCCOC2=CC=C(C=C2)Cl
Properties
C17H23ClO4
Molar mass 326.82 g·mol−1
Melting point 311 K[1]
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Etomoxir, or rac-Ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, in form of the dextrorotatory (R)-(+)- enantiomer, is an irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1; EC 2.3.1.21) on the inner face of the outer mitochondrial membrane.[2] The actual inhibitor – (R)-(+)-etomoxir-Coenzym A ester – is formed in an intracellular process. The middle inhibitor concentration for the inhibition of the CPT-1 in the liver, heart, and muscle mitochondria of rats lies in between 5 and 20 nmol/l (for rac-Etomoxir), depending on the animal's state of metabolism (fed or fasting). (+)-Etomoxir is a colourness solid with a melting point of 38 °C (311 K). The sodium salt of (+)-Etomoxir is water-soluble.[1] The (S)-(-)-enantiomer of Etomoxir does not block CPT-1.[3]

Etomoxir's mechanism prevents the formation of acyl carnitines, a step that is necessary for the transport of fatty acyl chains from the cytosol into the intermembrane space of the mitochondria. This step is essential to the production of ATP from fatty acid oxidation. Etomoxir has also been identified as a direct agonist of PPARα.[4] An off-target effect has been demonstrated at high concentrations of Etomoxir on Coenzyme-A (CoA) metabolism,[5] and on complex I of the electron transport chain.[6]

The influence of Etomoxir on food uptake is a matter of discussion. Contradictory findings were reported.[7][8]

Clinical development

[edit]

The primary effect of Etomoxir in vivo is a decrease in ketone bodies in the blood, followed by a decrease in blood glucose levels. These pharmacodynamic effects of (+)-Etomoxir can be explained by its mechanism and as a consequence of the inhibition of long-chain fatty acid oxidation. This results in a depression of ketogenesis and gluconeogenesis in the liver, and via disinhibition of the pyruvate dehydrogenase in an activation of glucose oxidation in the muscle.[9] In 1980, this prompted German firm Byk Gulden Lomberg Chemische Fabrik GmbH – the patent owner –[10] to initiate drug development for the treatment of type 2 diabetes. Because of the insufficient anti-diabetic efficacy and due to the fact that in the toxicological trials a heart hypertrophy in rats was found, Byk Gulden decided to cease development in 1992, before entering phase III clinical research.[11] The company had found by then a mild anti-diabetic effect and a good safety profile with exception of few cases of transient increases of liver transaminase (GPT). The most promising effect found was the lowering of triglyceride levels in blood.[12][13]

The results of the first clinical trial with Etomoxir in patients with chronic congestive heart failure were published in 2000.[14] Throughout the following years, it was found that Etomoxir has beneficial effects either in isolated perfused rat hearts or in vivo in animals and humans.[15][16][17]

By 1999, the inventor had granted a license to MediGene AG (Martinsried, Germany) for further development as a drug against congestive heart failure and hyperlipidemia. Phase II clinical research started 2001, and in 2002, Medigene AG announced that it had terminated this trial due to adverse side effects, i.e., unacceptable high liver transaminase levels in 4 patents in the verum group. The 2007 publication of the statistical evaluation, however, indicates that there were no significant differences between the placebo and verum groups.[18] Etomoxir causes an increase of GPT enzymes in the blood that is similar in effect to an increased enzyme concentration in the liver cells as a result of a cataboloic state.

Further developments

[edit]

Throughout the late 2000s, and 2010s, experimental evidence has accumulated indicating a broad spectrum of biological effects of Etomoxir.[11] Among the reported effects are effects on neurological diseases,[19] brain diseases,[20] inflammatory processes,[21] and metabolism of cancer cells.[6][22][23][24]

Danish 2 N Pharma are currently (2020) developing a drug against amyotrophic lateral sclerosis and parkinson's disease on the basis of Etomoxir.[25] The University of Colorado holds patents for use of a combination of Etomoxir with an inhibitor of glycolysis for the use as an anti-inflammatory and anti-carcinogenic agent.[21]

The therapeutic approach with a triple combination of Alisertib and Trametinib with Etomoxir proved to be beneficial, inducing regression of mouse advanced melanoma and remarkably prolonging the overall survival of mice.[23]

References

[edit]
  1. ^ a b Crilley, Martine M.L.; Edmunds, Andrew J.F.; Eistetter, Klaus; Golding, Bernard T. (1989). "Syntheses of enantiomers of 2-[6-(4-chlorophenoxy)hexyl]-oxirane-2-carboxylic acid". Tetrahedron Letters. 30 (7): 885–888. doi:10.1016/S0040-4039(01)80643-2.
  2. ^ Kruszynska YT, Sherratt HS (November 1987). "Glucose kinetics during acute and chronic treatment of rats with 2[6(4-chloro-phenoxy)hexyl]oxirane-2-carboxylate, etomoxir". Biochemical Pharmacology. 36 (22): 3917–21. doi:10.1016/0006-2952(87)90458-8. PMID 3689429.
  3. ^ Nüsing, Rolf: "Enzyme-kinetic investigations on inhibition of mitochondrial carnitine-palmitoyltransferase I by Etomoxir-CoA." Diploma Thesis (1985-07-12), Faculty of Biology, University of Constance
  4. ^ Portilla, Didier; Dai, Gonghe; Peters, Jeffrey M.; Gonzalez, Frank J.; Crew, Mark D.; Proia, Alan D. (2000-04-01). "Etomoxir-induced PPARα-modulated enzymes protect during acute renal failure". American Journal of Physiology. Renal Physiology. 278 (4): F667–F675. doi:10.1152/ajprenal.2000.278.4.F667. ISSN 1931-857X.
  5. ^ Divakaruni AS, Hsieh WY, Minarrieta L, Duong TN, Kim KK, Desousa BR, Andreyev AY, Bowman CE, Caradonna K, Dranka BP, Ferrick DA, Liesa M, Stiles L, Rogers GW, Braas D, Ciaraldi TP, Wolfgang MJ, Sparwasser T, Berod L, Bensinger SJ, Murphy AN (September 2018). "Etomoxir Inhibits Macrophage Polarization by Disrupting CoA Homeostasis". Cell Metabolism. 28 (3): 490–503.e7. doi:10.1016/j.cmet.2018.06.001. PMC 6125190. PMID 30043752.
  6. ^ a b Yao, Cong-Hui; Liu, Gao-Yuan; Wang, Rencheng; Moon, Sung Ho; Gross, Richard W.; Patti, Gary J. (2018-03-29). "Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of β-oxidation". PLOS Biology. 16 (3): e2003782. doi:10.1371/journal.pbio.2003782. ISSN 1545-7885. PMC 5892939. PMID 29596410.
  7. ^ Kahler A, Zimmermann M, Langhans W (1999). "Suppression of hepatic fatty acid oxidation and food intake in men". Nutrition. 15 (11–12): 819–28. doi:10.1016/s0899-9007(99)00212-9. PMID 10575655.
  8. ^ Gao, Su; Serra, Dolors; Keung, Wendy; Hegardt, Fausto G.; Lopaschuk, Gary D. (2013-08-01). "Important role of ventromedial hypothalamic carnitine palmitoyltransferase-1a in the control of food intake". American Journal of Physiology. Endocrinology and Metabolism. 305 (3): E336–E347. doi:10.1152/ajpendo.00168.2013. hdl:2445/54185. ISSN 0193-1849.
  9. ^ Wolf, H. P., & Engel, D. W. (1985). Decrease of fatty acid oxidation, ketogenesis and gluconeogenesis in isolated perfused rat liver by phenylalkyl oxirane carboxylate (B 807-27) due to inhibition of CPT I (EC 2.3. 1.21). European Journal of Biochemistry, 146(2).
  10. ^ EP 0025192B1 
  11. ^ a b "Etomoxir". Dr. Wolf Bioscience (in German and English). Retrieved 2024-03-22.
  12. ^ EP 0231367B1 
  13. ^ Ratheiser, K.; Schneeweiß, B.; Waldhäusl, W.; Fasching, P.; Korn, A.; Nowotny, P.; Rohac, M.; Wolf, H.P.O. (1991). "Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus". Metabolism. 40 (11): 1185–1190. doi:10.1016/0026-0495(91)90214-H.
  14. ^ Schmidt-Schweda, Stephan; Holubarsch, Christian (2000-07-01). "First clinical trial with etomoxir in patients with chronic congestive heart failure". Clinical Science. 99 (1): 27–35. doi:10.1042/cs0990027. ISSN 0143-5221.
  15. ^ Tuunanen, Helena; Knuuti, Juhani (2011-01-01). "(PDF) Metabolic modulation in dilated cardiomyopathy". Heart and Metabolism (49). Servier International: 17–19. ISSN 1566-0338.
  16. ^ Bristow, Michael (2000). "Etomoxir: a new approach to treatment of chronic heart failure". The Lancet. 356 (9242): 1621–1622. doi:10.1016/S0140-6736(00)03149-4.
  17. ^ Rupp, Heinz; Rupp, Thomas P.; Alter, Peter; Maisch, Bernhard (2006). "Acute Heart Failure—Basic Pathomechanism and New Drug Targets". Herz Kardiovaskuläre Erkrankungen. 31 (8): 727–735. doi:10.1007/s00059-006-2911-x. ISSN 0340-9937.
  18. ^ Holubarsch CJ, Rohrbach M, Karrasch M, Boehm E, Polonski L, Ponikowski P, Rhein S (August 2007). "A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study". Clinical Science. 113 (4): 205–12. doi:10.1042/CS20060307. PMID 17319797. S2CID 25689289.
  19. ^ Shriver, Leah P.; Manchester, Marianne (2011-09-01). "Inhibition of fatty acid metabolism ameliorates disease activity in an animal model of multiple sclerosis". Scientific Reports. 1 (1): 79. doi:10.1038/srep00079. ISSN 2045-2322. PMC 3216566.
  20. ^ Trabjerg, Michael Sloth; Andersen, Dennis Christian; Huntjens, Pam; Mørk, Kasper; Warming, Nikolaj; Kullab, Ulla Bismark; Skjønnemand, Marie-Louise Nibelius; Oklinski, Michal Krystian; Oklinski, Kirsten Egelund; Bolther, Luise; Kroese, Lona J.; Pritchard, Colin E. J.; Huijbers, Ivo J.; Corthals, Angelique; Søndergaard, Mads Toft; Kjeldal, Henrik Bech; Pedersen, Cecilie Fjord Morre; Nieland, John Dirk Vestergaard (2023-01-21). "Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson's disease". npj Parkinson's Disease. 9 (1). doi:10.1038/s41531-023-00450-y. ISSN 2373-8057. PMC 9867753. PMID 36681683.
  21. ^ a b Newell, Martha K., Evan Newell, and Elizabeth Villobos-Menvey. Etomoxir and a 2-deoxy-D-glucose Compound; Antiinflammatory, Antiproliferative, Anticarcinogenic and Wound Healing Agents; Drug Resistant Cancers. The Regents Of The University Of Colorado, assignee. Patent US7510710 B2. 31 Mar. 2009.
  22. ^ Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G (November 2013). "Metabolic targets for cancer therapy". Nature Reviews. Drug Discovery. 12 (11): 829–46. doi:10.1038/nrd4145. PMID 24113830. S2CID 10921547.
  23. ^ a b Camarda, Roman; Zhou, Alicia Y; Kohnz, Rebecca A; Balakrishnan, Sanjeev; Mahieu, Celine; Anderton, Brittany; Eyob, Henok; Kajimura, Shingo; Tward, Aaron; Krings, Gregor; Nomura, Daniel K; Goga, Andrei (2016). "Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer". Nature Medicine. 22 (4): 427–432. doi:10.1038/nm.4055. ISSN 1078-8956. PMC 4892846. PMID 26950360.
  24. ^ Estañ, María Cristina; Calviño, Eva; Calvo, Susana; Guillén-Guío, Beatriz; Boyano-Adánez, María del Carmen; de Blas, Elena; Rial, Eduardo; Aller, Patricio (2014-12-15). "Apoptotic Efficacy of Etomoxir in Human Acute Myeloid Leukemia Cells. Cooperation with Arsenic Trioxide and Glycolytic Inhibitors, and Regulation by Oxidative Stress and Protein Kinase Activities". PLoS ONE. 9 (12): e115250. doi:10.1371/journal.pone.0115250. ISSN 1932-6203. PMC 4266683. PMID 25506699.
  25. ^ Trabjerg, Michael Sloth; Mørkholt, Anne Skøttrup; Lichota, Jacek; Oklinski, Michal Krystian Egelund; Andersen, Dennis Christian; Jønsson, Katrine; Mørk, Kasper; Skjønnemand, Marie-Louise Nibelius; Kroese, Lona John; Pritchard, Colin Eliot Jason; Huijbers, Ivo Johan; Gazerani, Parisa; Corthals, Angelique; Nieland, John Dirk Vestergaard (2020-09-24). "Dysregulation of metabolic pathways by carnitine palmitoyl-transferase 1 plays a key role in central nervous system disorders: experimental evidence based on animal models". Scientific Reports. 10 (1). Springer Science and Business Media LLC: 1–19. doi:10.1038/s41598-020-72638-8. ISSN 2045-2322. PMC 7519132.
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