# Etomoxir

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. 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. The (S)-(-)-enantiomer of Etomoxir does not block CPT-1.
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. An off-target effect has been demonstrated at high concentrations of Etomoxir on Coenzyme-A (CoA) metabolism, and on complex I of the electron transport chain.
The influence of Etomoxir on food uptake is a matter of discussion. Contradictory findings were reported.

## 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 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. In 1980, this prompted German firm Byk Gulden Lomberg Chemische Fabrik GmbH – the patent owner – 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. 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.
The results of the first clinical trial with Etomoxir in patients with chronic congestive heart failure were published in 2000. 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.
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. 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

Throughout the late 2000s, and 2010s, experimental evidence has accumulated indicating a broad spectrum of biological effects of Etomoxir. Among the reported effects are effects on neurological diseases, brain diseases, inflammatory processes, and metabolism of cancer cells.
Danish 2 N Pharma are currently (2020) developing a drug against amyotrophic lateral sclerosis and parkinson's disease on the basis of Etomoxir. 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.
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.