Etomoxir

Last updated
Etomoxir
Etomoxir.svg
Names
IUPAC name
rac-Ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.225.462 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
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 the 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 biologically active inhibitor – (R)-(+)-etomoxir-Coenzyme A ester – is formed through an intracellular process. The mean concentration for the inhibition of the CPT-1 in the liver, heart, and muscle mitochondria of rats is 20 micromolar/kilogram rac-Etomoxir. [3] (+)-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. [4]

Contents

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, causing cell cycle arrest in cancer cells. [5] At higher concentrations of the drug, off-target effects have been demonstrated on Coenzyme-A (CoA) metabolism [6] and on Complex I of the electron transport chain. [7]

The influence of Etomoxir on food uptake is a matter of discussion, as contradictory findings have been reported. [8] [9]

Clinical development

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 disinhibition of the pyruvate dehydrogenase and an activation of glucose oxidation in the muscle. [10] In 1980, this prompted German firm Byk Gulden Lomberg Chemische Fabrik GmbH – the patent owner – [11] to initiate drug development for the treatment of type 2 diabetes. The company identified a mild anti-diabetic effect and a good safety profile with exception of few cases of transient increases in liver transaminase levels [12] . The most promising effect found was the lowering of triglyceride levels in blood. [13] [14]

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. Etomoxir entered its first clinical trial for patients with congestive heart failure, with results published in 2000. [15] 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. [16] [17] [18]

Phase II clinical research started in 2001, with 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 congestive heart failure. This was called the ERGO (etomoxir for the recovery of glucose oxidation) study. 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 of 226 patients treated with the drug. The 2007 publication of the study, however, indicates the effects were reversible and statistical evaluation showed there were no significant differences between the placebo and treatment groups. [19] The published study also reported that fewer patients died in the drug treatment group than in the placebo group, with 3/121 patients (2.5%) dying in the placebo group, 1/118 patients (0.8%) dying in the 40 mg etomoxir treatment group and 1/108 (0.9%) dying in the 80 mg treatment group. [19] The deaths were all due to cardiac events in these patients with congestive heart failure.

Further developments

Throughout the late 2000s, and 2010s, experimental evidence has accumulated indicating a broad spectrum of biological effects of Etomoxir. [12] Among the reported effects are reduced disease progression in multiple sclerosis, [20] a reversal of autoimmune encephalitis, [21] and resistance to onset of Parkinson's disease. [22] In addition, etomoxir inhibits tumor growth in animal models of breast cancer, [23] prostate cancer, [24] ovarian cancer, [25] bladder cancer, [26] and brain cancer. [27] [28] [29] These anti-cancer effects of etomoxir are not only due to mechanisms within the cancer cells themselves, [30] but also due to a reduction of tumor-associated macrophages in the pro-inflammatory tumor microenvironment. [30]

The University of Colorado filed a patent in 2005 to use a combination of Etomoxir and an inhibitor of glycolysis as an anti-inflammatory and anti-carcinogenic agent, but this patent has since expired. [31] Numiera Therapeutics, a US based pharmaceutical company, announced in 2025 that they secured orphan drug designation on etomoxir for treating malignant glioma, and that they are planning clinical trials in neuro oncology. [32] [33]

References

  1. 1 2 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. ↑ Oakes ND, Kjellstedt A, Forsberg GB, Clementz T, Camejo G, Furler SM, Kraegen EW, Halvarsson M, Jenkins AB, Ljung B (June 1999). "Development and initial evaluation of a novel method for assessing tissue-specific plasma free fatty acid utilization in vivo using (R) 2-bromopalmitate tracer". J Lipid Research. 40 (6): 1155–1169. doi:10.1016/2FS0022-2275(20)33520-3. PMID   10357848.
  4. ↑ 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
  5. ↑ Cheng, Songtao; Wang, Gang; Wang, Xinghuan (2019-08-07). "Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer". Clinical Science (Lond). Clin Sci. 133 (15): 1745–1758. doi:10.1042/CS20190587. ISSN   1931-857X. PMID   31358595.
  6. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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. PMID   23736540.
  10. ↑ 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).
  11. ↑ EP 0025192B1
  12. 1 2 "Etomoxir". Dr. Wolf Bioscience (in German and English). Retrieved 2024-03-22.
  13. ↑ EP 0231367B1
  14. ↑ 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. PMID   1943747.
  15. ↑ 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. PMID   10887055.
  16. ↑ Tuunanen, Helena; Knuuti, Juhani (2011-01-01). "Metabolic modulation in dilated cardiomyopathy". Heart and Metabolism (49). Servier International: 17–19. ISSN   1566-0338.
  17. ↑ 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. PMID   11089814.
  18. ↑ 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. PMID   17149674.
  19. 1 2 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" (PDF). Clinical Science. 113 (4): 205–12. doi:10.1042/CS20060307. PMID   17319797. S2CID   25689289.
  20. ↑ 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. Bibcode:2011NatSR...1...79S. doi:10.1038/srep00079. ISSN   2045-2322. PMC   3216566 . PMID   22355598.
  21. ↑ Mørkholt, Anne Skøttrup; Oklinski, Michal Krystian; Larsen, Agnete; Bockermann, Robert; Issazadeh-Navikas, Shohreh; Nieland, Jette Goller Kloth; Kwon, Tae-Hwan; Corthals, Angelique; Nielsen, Søren; Nieland, John Dirk Vestergaard (2020). "Pharmacological inhibition of carnitine palmitoyl transferase 1 inhibits and reverses experimental autoimmune encephalitis in rodents". PLOS ONE. 15 (6) e0234493. Bibcode:2020PLoSO..1534493M. doi: 10.1371/journal.pone.0234493 . ISSN   1932-6203. PMC   7286491 . PMID   32520953.
  22. ↑ 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): 6. doi:10.1038/s41531-023-00450-y. ISSN   2373-8057. PMC   9867753 . PMID   36681683.
  23. ↑ 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.
  24. ↑ Flaig, Thomas W.; Salzmann-Sullivan, Maren; Su, Lih-Jen; Zhang, Zhiyong; Joshi, Molishree; Gijón, Miguel A.; Kim, Jihye; Arcaroli, John J.; Van Bokhoven, Adrie; Lucia, M. Scott; La Rosa, Francisco G.; Schlaepfer, Isabel R. (2017-08-22). "Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade". Oncotarget. 8 (34): 56051–56065. doi:10.18632/oncotarget.17359. ISSN   1949-2553. PMC   5593544 . PMID   28915573.
  25. ↑ Sawyer, Brandon T.; Qamar, Lubna; Yamamoto, Tomomi M.; McMellen, Alexandra; Watson, Zachary L.; Richer, Jennifer K.; Behbakht, Kian; Schlaepfer, Isabel R.; Bitler, Benjamin G. (July 2020). "Targeting Fatty Acid Oxidation to Promote Anoikis and Inhibit Ovarian Cancer Progression". Molecular Cancer Research. 18 (7): 1088–1098. doi:10.1158/1541-7786.MCR-19-1057. ISSN   1557-3125. PMC   7335321 . PMID   32198139.
  26. ↑ Cheng, Songtao; Wang, Gang; Wang, Yejinpeng; Cai, Liwei; Qian, Kaiyu; Ju, Lingao; Liu, Xuefeng; Xiao, Yu; Wang, Xinghuan (2019-08-15). "Fatty acid oxidation inhibitor etomoxir suppresses tumor progression and induces cell cycle arrest via PPARγ-mediated pathway in bladder cancer". Clinical Science. 133 (15): 1745–1758. doi: 10.1042/CS20190587 . ISSN   1470-8736. PMID   31358595.
  27. ↑ Lin, Hua; Patel, Shaan; Affleck, Valerie S.; Wilson, Ian; Turnbull, Douglass M.; Joshi, Abhijit R.; Maxwell, Ross; Stoll, Elizabeth A. (January 2017). "Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells". Neuro-Oncology. 19 (1): 43–54. doi:10.1093/neuonc/now128. ISSN   1523-5866. PMC   5193020 . PMID   27365097.
  28. ↑ Kant, Shiva; Kesarwani, Pravin; Prabhu, Antony; Graham, Stewart F.; Buelow, Katie L.; Nakano, Ichiro; Chinnaiyan, Prakash (2020-04-20). "Enhanced fatty acid oxidation provides glioblastoma cells metabolic plasticity to accommodate to its dynamic nutrient microenvironment". Cell Death & Disease. 11 (4): 253. doi:10.1038/s41419-020-2449-5. ISSN   2041-4889. PMC   7170895 . PMID   32312953.
  29. ↑ Shim, Jin-Kyoung; Choi, Seonah; Yoon, Seon-Jin; Choi, Ran Joo; Park, Junseong; Lee, Eun Hee; Cho, Hye Joung; Lee, Suji; Teo, Wan-Yee; Moon, Ju Hyung; Kim, Hyun Sil; Kim, Eui Hyun; Cheong, Jae-Ho; Chang, Jong Hee; Yook, Jong In (2022-10-11). "Etomoxir, a carnitine palmitoyltransferase 1 inhibitor, combined with temozolomide reduces stemness and invasiveness in patient-derived glioblastoma tumorspheres". Cancer Cell International. 22 (1): 309. doi: 10.1186/s12935-022-02731-7 . ISSN   1475-2867. PMC   9552483 . PMID   36221088.
  30. 1 2 Zhang, Qi; Wang, Herui; Mao, Chengyuan; Sun, Mitchell; Dominah, Gifty; Chen, Liyuan; Zhuang, Zhengping (February 2018). "Fatty acid oxidation contributes to IL-1β secretion in M2 macrophages and promotes macrophage-mediated tumor cell migration". Molecular Immunology. 94: 27–35. doi:10.1016/j.molimm.2017.12.011. ISSN   1872-9142. PMC   5801116 . PMID   29248877.
  31. ↑ 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.
  32. ↑ Innosphere (2025-01-10). "Numiera Therapeutics Announces Orphan Drug Designation and Matching Funds from the State of Colorado to Advance Innovative Brain Cancer Treatment". GlobeNewswire News Room (Press release). Retrieved 2025-05-21.
  33. ↑ "Search Orphan Drug Designations and Approval". Us Food and Drug Administration.[ dead link ]
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