Etomoxir, or 2 (4-chlorophenoxy)hexylxirane-2-carboxylate, is an irreversible inhibitor of carnitine palmitoyltransferase-1 (CPT-1) on the inner face of the

outer mitochondrial membrane A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used t ...

. 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 A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...

. This step is essential to the production of

ATP ATP may refer to: Companies and organizations * Association of Tennis Professionals, men's professional tennis governing body * American Technical Publishers, employee-owned publishing company * ', a Danish pension * Armenia Tree Project, non ...

from fatty acid oxidation. Etomoxir has also been identified as a direct agonist of

PPARα Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gene ...

. An off-target effect has been demonstrated at high concentrations of etomoxir on Coenzyme-A (CoA) metabolism. 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%. Etomoxir has been reported to decrease the incorporation of

palmitic acid Palmitic acid (hexadecanoic acid in IUPAC nomenclature) is a fatty acid with a 16-carbon chain. It is the most common saturated fatty acid found in animals, plants and microorganisms.Gunstone, F. D., John L. Harwood, and Albert J. Dijkstra. The Li ...

and

oleic acid Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish. In chemical terms, oleic acid is classified as a monounsaturated omega ...

into

cardiolipin Cardiolipin (IUPAC name 1,3-bis(''sn''-3’-phosphatidyl)-''sn''-glycerol) is an important component of the inner mitochondrial membrane, where it constitutes about 20% of the total lipid composition. It can also be found in the membranes of most ...

, although it does not affect the activities of cardiolipin biosynthesis and remodeling. Etomoxir has off-target effects. At high concentrations, etomoxir inhibits complex I of the electron transport chain. 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 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...

and

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

. Etomoxir went through preclinical trials by Byk Gulden laboratories (now Altana Pharma AG) from 1981 to 1984. 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. In 1999, the

patent A patent is a type of intellectual property that gives its owner the legal right to exclude others from making, using, or selling an invention for a limited period of time in exchange for publishing an enabling disclosure of the invention."A p ...

was out-licensed to MediGene for further trials. In 2001, MediGene was granted extended patent rights for the use of etomoxir for the treatment of

congestive heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...

. In 2002, MediGene announced that it terminated a phase II trial for the use of etomoxir for heart failure due to adverse

side effects In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...

. 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. The

University of Colorado The University of Colorado (CU) is a system of public universities in Colorado. It consists of four institutions: University of Colorado Boulder, University of Colorado Colorado Springs, University of Colorado Denver, and the University of Co ...

currently holds patents for the use of etomoxir as an anti-inflammatory and anticarcinogenic agent.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. However, the clinical development of etomoxir has been terminated due to severe hepatotoxicity associated with treatment.

References

{{PPAR modulators Epoxides Ethyl esters Chloroarenes Phenol ethers Enzyme inhibitors