Di-deuterated linoleic acid ethyl ester

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Di-deuterated linoleic acid ethyl ester
Di-deuterated linoleate ester.png
Clinical data
Routes of
administration
Oral
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
CAS Number
PubChem CID
UNII
Chemical and physical data
FormulaC20H34D2O2
Molar mass310.5148 g/mol g·mol−1
3D model (JSmol)
Density0.88 g/cm3
Boiling point173–177 °C (343–351 °F)
 ☒N☑Y (what is this?)

Di-deuterated ethyl linoleate (also known as RT001; di-deuterated linoleic acid ethyl ester, 11,11-d2-ethyl linoleate, ethyl 11,11-d2-linoleate)[1] is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), an isotopologue of an essential omega-6 PUFA, linoleic acid. The deuterated compound, while identical to natural linoleic acid, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

Mechanism of action[edit]

Di-deuterated linoleic acid is recognized by cells as identical to the natural linoleic acid. But when taken up, it is converted into 13,13-D2-arachidonic acid, a heavy isotope version of arachidonic acid, that gets incorporated into lipid membranes. The deuterated compound resists the non-enzymatic lipid peroxidation (LPO) through 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 as reactive carbonyls.[2]

Clinical development[edit]

Friedreich’s ataxia[edit]

A double-blind comparator-controlled Phase I/II clinical trial for Friedreich’s ataxia, sponsored by Retrotope and Friedreich’s Ataxia Research Alliance, was conducted to determine the safety profile and appropriate dosing for consequent trials.[3] RT001 was promptly absorbed and was found to be safe and tolerable over 28 days at the maximal dose of 9 g/day. It improved peak workload and peak oxygen consumption in the test group compared to the control group who received the equal doses of normal, non-deuterated ethyl linoleate.[4]

Infantile neuroaxonal dystrophy[edit]

An open-label clinical study for infantile neuroaxonal dystrophy evaluating long-term evaluation of efficacy, safety, tolerability, and pharmacokinetics of RT001, which, when taken with food, can protect the neuronal cells from degeneration, started in the Summer 2018.[5]

Phospholipase 2G6-associated neurodegeneration[edit]

In 2017 FDA granted RT001 orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN).[6]

Amyotrophic lateral sclerosis[edit]

In 2018 RT001 was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme".[7]

Preclinical research[edit]

Alzheimer's disease[edit]

RT001 has been shown to be effective in a model of Alzheimer's disease in mice.[8]

References[edit]

  1. ^ "9-cis, 12-cis-11,11-D2-Linoleic acid ethyl ester".
  2. ^ PMID 22705367
  3. ^ https://clinicaltrials.gov/ct2/show/NCT02445794
  4. ^ Zesiewicz, Theresa; Heerinckx, Frederic; De Jager, Robert; Omidvar, Omid; Kilpatrick, Marcus; Shaw, Jessica; Shchepinov, Mikhail S. (2018). "Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia". Movement Disorders. 33 (6): 1000–1005. doi:10.1002/mds.27353. PMID 29624723.
  5. ^ https://clinicaltrials.gov/ct2/show/NCT03570931
  6. ^ "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration". Global Newswire. 2 November 2017.
  7. ^ "Experimental RT001 Now Available for ALS Under Expanded Access". 2018-09-18.
  8. ^ Butterfield, D. Allan; Halliwell, Barry (2019). "Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease". Nature Reviews Neuroscience. 20 (3): 148–160. doi:10.1038/s41583-019-0132-6. PMID 30737462.