Deulinoleate ethyl

Last updated
Deulinoleate ethyl
Di-deuterated linoleate ester.svg
Clinical data
Other namesRT001; 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
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • Ethyl (9Z,12Z)-9,12-11,11-d2-octadecadienoate
CAS Number
PubChem CID
UNII
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)
  • CCCCCC=CCC=CCCCCCCCC(=O)OCC
  • InChI=1S/C20H36O2/c1-3-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-20(21)22-4-2/h8-9,11-12H,3-7,10,13-19H2,1-2H3/b9-8-,12-11-/i10D2
  • Key:FMMOOAYVCKXGMF-XMCVDNGOSA-N
 X mark.svgNYes check.svgY  (what is this?)

Deulinoleate ethyl (also known as di-deuterated ethyl linoleate, di-deuterated linoleic acid ethyl ester, 11,11-d2-ethyl linoleate, or ethyl 11,11-d2-linoleate) [1] is an experimental, orally-bioavailable synthetic deuterated polyunsaturated fatty acid (PUFA), a part of reinforced lipids. It is an isotopologue of linoleic acid, an essential omega-6 PUFA. The deuterated compound, while identical to natural linoleic acid except for the presence of deuterium, is resistant to lipid peroxidation which makes studies of its cell-protective properties worthwhile.

Contents

Mechanism of action

An animated illustration of a chain reaction with slow elements

Deulinoleate ethyl 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 isotope 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 as reactive 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]

Clinical development

Friedreich's ataxia

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. [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 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. [6] Another randomized, double-blind, placebo-controlled clinical study began in 2019. [7]

Infantile neuroaxonal dystrophy

An open-label clinical study for infantile 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]

Phospholipase 2G6-associated neurodegeneration

In 2017, the FDA granted deulinoleate ethyl orphan drug designation in the treatment of phospholipase 2G6-associated neurodegeneration (PLAN). [9]

Amyotrophic lateral sclerosis

In 2018, deulinoleate ethyl was given to a patient with amyotrophic lateral sclerosis (ALS) under a "compassionate use scheme". [10]

Progressive supranuclear palsy

In 2020, the FDA granted orphan drug designation deulinoleate ethyl for the treatment of patients with progressive 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]

Preclinical research

Alzheimer's disease

Deulinoleate ethyl has been shown to be effective in a model of Alzheimer's disease in mice. [12]

Related Research Articles

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<span class="mw-page-title-main">Deuterated drug</span>

A deuterated drug is a small molecule medicinal product in which one or more of the hydrogen atoms contained in the drug molecule have been replaced by its heavier stable isotope deuterium. Because of the kinetic isotope effect, deuterium-containing drugs may have significantly lower rates of metabolism, and hence a longer half-life.

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<span class="mw-page-title-main">Deutetrabenazine</span> Chemical compound

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<span class="mw-page-title-main">Isotope effect on lipid peroxidation</span>

Isotope effect is observed when molecules containing heavier isotopes of the same atoms are engaged in a chemical reaction at a slower rate. Deuterium-reinforced lipids can be used for the protection of living cells by slowing the chain reaction of lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, drugs that stop the chain reaction of lipid peroxidation have preventive and therapeutic potential.

<span class="mw-page-title-main">Reinforced lipids</span> Deuterated lipid molecules

Reinforced lipids are lipid molecules in which some of the fatty acids contain deuterium instead of hydrogen. They can be used for the protection of living cells by slowing the chain reaction due to isotope effect on lipid peroxidation. The lipid bilayer of the cell and organelle membranes contain polyunsaturated fatty acids (PUFA) are key components of cell and organelle membranes. Any process that either increases oxidation of PUFAs or hinders their ability to be replaced can lead to serious disease. Correspondingly, use of reinforced lipids that stop the chain reaction of lipid peroxidation has preventive and therapeutic potential.

References

  1. "9-cis, 12-cis-11,11-D2-Linoleic acid ethyl ester". PubChem.
  2. Hill S, Lamberson CR, Xu L, To R, Tsui HS, Shmanai VV, et al. (August 2012). "Small amounts of isotope-reinforced polyunsaturated fatty acids suppress lipid autoxidation". Free Radical Biology & Medicine. 53 (4): 893–906. doi:10.1016/j.freeradbiomed.2012.06.004. PMC   3437768 . PMID   22705367.
  3. Demidov VV (August 2020). "Site-specifically deuterated essential lipids as new drugs against neuronal, retinal and vascular degeneration". Drug Discovery Today. 25 (8): 1469–1476. doi:10.1016/j.drudis.2020.03.014. PMID   32247036. S2CID   214794450.
  4. Scarpellini C, Klejborowska G, Lanthier C, Hassannia B, Vanden Berghe T, Augustyns K (September 2023). "Beyond ferrostatin-1: a comprehensive review of ferroptosis inhibitors". Trends in Pharmacological Sciences: S0165–6147(23)00182–7. doi: 10.1016/j.tips.2023.08.012 . hdl: 1854/LU-01HJ90DJVXAJ7NPCGA09GG3NFR . PMID   37770317.
  5. Clinical trial number NCT02445794 for "A First in Human Study of RT001 in Patients With Friedreich's Ataxia" at ClinicalTrials.gov
  6. Zesiewicz T, Heerinckx F, De Jager R, Omidvar O, Kilpatrick M, Shaw J, Shchepinov MS (July 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. S2CID   4664990.
  7. Clinical trial number NCT04102501 for "A Study to Assess Efficacy, Long Term Safety and Tolerability of RT001 in Subjects With Friedreich's Ataxia" at ClinicalTrials.gov
  8. Clinical trial number NCT03570931 for "A Study to Assess Efficacy and Safety of RT001 in Subjects With Infantile Neuroaxonal Dystrophy" at ClinicalTrials.gov
  9. "US FDA Grants Orphan Drug Designation for Retrotope's RT001 in the Treatment of Phospholipase 2G6 (PLA2G6)-Associated Neurodegeneration". Global Newswire. 2 November 2017. Archived from the original on 1 April 2019. Retrieved 12 March 2019.
  10. Inacio P (2018-09-18). "Experimental RT001 Now Available for ALS Under Expanded Access". ALS News Today.
  11. "RT001 Gets Orphan Drug Designation in Progressive Supranuclear Palsy".
  12. Butterfield DA, Halliwell B (March 2019). "Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease". Nature Reviews. Neuroscience. 20 (3): 148–160. doi:10.1038/s41583-019-0132-6. PMC   9382875 . PMID   30737462. S2CID   59617957.