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| Other names | RT001; Di-deuterated ethyl linoleate; Di-deuterated linoleic acid ethyl ester, 11,11-d2-Ethyl linoleate, or Ethyl 11,11-d2-linoleate |
| Routes of administration | Oral |
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| Chemical and physical data | |
| Formula | C20H34D2O2 |
| Molar mass | 310.517 g·mol−1 |
| 3D model (JSmol) | |
| Density | 0.88 g/cm3 |
| Boiling point | 173–177 °C (343–351 °F) |
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Deulinoleate ethyl (also known asdi-deuterated ethyl linoleate,di-deuterated linoleic acid ethyl ester,11,11-d2-ethyl linoleate, orethyl 11,11-d2-linoleate)[1] is an experimental, orally-bioavailable syntheticdeuteratedpolyunsaturated fatty acid (PUFA), a part ofreinforced lipids. It is anisotopologue oflinoleic acid, anessentialomega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant tolipid peroxidation which makes studies of itscell-protective properties worthwhile.
Deulinoleate ethyl is recognized by cells as identical to normal linoleic acid. But when taken up, it is converted into 13,13-d2-arachidonic acid, a heavy isotope version ofarachidonic acid, that gets incorporated into lipid membranes. The deuterated compound resists the non-enzymaticlipid peroxidation (LPO) throughisotope effect — a non-antioxidant based mechanism that protects mitochondrial, neuronal and other lipid membranes, thereby greatly reducing the levels of numerous LPO-derived toxic products such asreactive carbonyls.[2][3]
Deulinoleate ethyl inhibits ferroptosis by stopping the autoxidation process through the kinetic isotope effect. The protective effect of D-PUFAs was verified in erastin- and RSL3-induced ferroptosis models, with demonstrated efficacy in various disease models, particularly neurodegenerative disorders and clinical trials of deulinoleate ethyl begun in 2018.[4]
A double-blindcomparator-controlled Phase I/II clinical trial forFriedreich's ataxia, sponsored byRetrotope andFriedreich's Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials.[5] Deulinoleate ethyl was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improvedpeak workload andpeak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated ethyl linoleate.[6] Another randomized, double-blind, placebo-controlled clinical study began in 2019.[7]
An open-label clinical study forinfantile neuroaxonal dystrophy evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of deulinoleate ethyl, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.[8]
In 2017, theFDA granted deulinoleate ethylorphan drug designation in the treatment ofphospholipase 2G6-associated neurodegeneration (PLAN).[9]
In 2018, deulinoleate ethyl was given to a patient withamyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[10]
In 2020, the FDA granted orphan drug designation deulinoleate ethyl for the treatment of patients withprogressive supranuclear palsy (PSP). PSP is a disease involving modification and dysfunction of tau protein; mechanism of action of deulinoleate ethyl both lowers lipid peroxidation and prevents mitochondrial cell death of neurons which is associated with disease onset and progression.[11]
Deulinoleate ethyl has been shown to be effective in a model ofAlzheimer's disease in mice.[12]
