Etomoxir

Etomoxir, or 2[6(4-chlorophenoxy)hexyl]oxirane-2-carboxylate, is an irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1) on the inner face of the outer mitochondrial membrane.[1] This 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.[2] An off-target effect has been demonstrated at high concentrations of etomoxir on Coenzyme-A (CoA) metabolism.[3]

Etomoxir
Names
IUPAC name
Ethyl 2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate
Identifiers
CAS Number
3D model (JSmol)
ChEMBL
ChemSpider
ECHA InfoCard 100.225.462
PubChem CID
UNII
InChI
  • 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
SMILES
  • CCOC(=O)[C@]1(CO1)CCCCCCOC2=CC=C(C=C2)Cl
Properties
Chemical formula
 C17H23ClO4
Molar mass 326.82 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

A double-blind crossover study in human adult males showed that treatment with etomoxir enhanced feelings of hunger and increased meal portion size by 22%.[4]

Etomoxir has been reported to decrease the incorporation of palmitic acid and oleic acid into cardiolipin, although it does not affect the activities of cardiolipin biosynthesis and remodeling.[5]

Etomoxir has off-target effects. At high concentrations, etomoxir inhibits complex I of the electron transport chain.[6] Caution should be exercised when interpreting the metabolic effects of this compound.

Licensing and clinical development

Etomoxir has already been through phase II clinical development for the treatment of type 2 diabetes and heart failure. Etomoxir went through preclinical trials by Byk Gulden laboratories (now Altana Pharma AG) from 1981 to 1984.[7] From 1984 to 1993, etomoxir was developed through phase I and II trials that showed favorable effects on the heart and a good safety profile.[8] In 1999, the patent was out-licensed to MediGene for further trials.[7] In 2001, MediGene was granted extended patent rights for the use of etomoxir for the treatment of congestive heart failure.[9] In 2002, MediGene announced that it terminated a phase II trial for the use of etomoxir for heart failure due to adverse side effects.[10] MediGene funded a study of etomoxir as a treatment of heart failure in 2007, but the study was once again terminated prematurely. Four of the 226 patients taking the drug showed unacceptably high liver transaminase levels, which was determined by the experimenters to likely be due to the treatment.[11] The University of Colorado currently holds patents for the use of etomoxir as an anti-inflammatory and anticarcinogenic agent.[12] However, the clinical development of etomoxir has been terminated due to severe hepatotoxicity associated with treatment.[13]

References
  1. 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.
  2. "(+)-Etomoxir (sodium salt)". Cayman Chemical. Cayman Chemical Company. 2015. Retrieved 18 March 2015.
  3. 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.
  4. 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.
  5. Xu FY, Taylor WA, Hurd JA, Hatch GM (February 2003). "Etomoxir mediates differential metabolic channeling of fatty acid and glycerol precursors into cardiolipin in H9c2 cells". Journal of Lipid Research. 44 (2): 415–23. doi:10.1194/jlr.M200335-JLR200. PMID 12576524.
  6. Yao, C. H., G. Y. Liu, et al. (2018). "Identifying off-target effects of etomoxir reveals that carnitine palmitoyltransferase I is essential for cancer cell proliferation independent of beta-oxidation." PLoS Biol 16(3): e2003782.
  7. "Drug candidates with blockbuster potential". bioscience-beteiligungs-anstalt.com. BioScience Beteiligungs Anstalt. 2015. Archived from the original on 2 April 2015. Retrieved 19 March 2015.
  8. "MediGene AG starts phase 2 clinical trial for its cardiac lead product Etomoxir". Evaluate. Evaluate Ltd. 12 December 2000. Retrieved 19 March 2015.
  9. "MediGene´s rights for Etomoxir extended to novel indications". Evaluate Group. Evaluate Ltd. 15 February 2001. Retrieved 19 March 2015.
  10. "MediGene's Etomoxir project delayed". Evaluate Group. Evaluate Ltd. 19 April 2002. Retrieved 19 March 2015.
  11. 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.
  12. 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.
  13. 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.
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