Olesoxime

Olesoxime
Identifiers
  • (NZ)-N-[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-ylidene]hydroxylamine
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC27H45NO
Molar mass399.663 g·mol−1
3D model (JSmol)
  • C[C@H](CCCC(C)C)[C@H]1CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2CCC4=C/C(=N\O)/CC[C@]34C)C
  • InChI=1S/C27H45NO/c1-18(2)7-6-8-19(3)23-11-12-24-22-10-9-20-17-21(28-29)13-15-26(20,4)25(22)14-16-27(23,24)5/h17-19,22-25,29H,6-16H2,1-5H3/t19-,22+,23-,24+,25+,26+,27-/m1/s1
  • Key:QNTASHOAVRSLMD-GYKMGIIDSA-N

Olesoxime (TRO19622) is an experimental drug formerly under development by the now-defunct French company Trophos as a treatment for a range of neuromuscular disorders. It has a cholesterol-like structure and belongs to the cholesterol-oxime family of mitochondrial pore modulators.[1][2]

Research

In preclinical studies, the compound displayed neuroprotective properties by promoting the function and survival of neurons and other cell types under disease-relevant stress conditions. It did so through interactions with two components of the mitochondrial permeability transition pore (mPTP), VDAC and TSPO.[3] In preclinical studies on Huntington's disease, the disease-attenuating effects of olesoxime were attributed to modulating the activity of calcium-dependent proteases called calpains.[4][5]

A 2009–2011 phase 3 clinical trial in amyotrophic lateral sclerosis did not demonstrate an increase in survival.[6] A 2011–2013 trial in spinal muscular atrophy (SMA) indicated that the compound may prevent deterioration of muscle function.[7][8] In 2015, the entire olesoxime programme was purchased by Hoffmann-La Roche for €120 million with a view to developing a treatment for SMA. However, in June 2018, faced with technical and regulatory challenges and competition from a potentially more effective drug nusinersen, Roche halted further development of olesoxime.[9]

References

  1. ^ Martin LJ (August 2010). "Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis". IDrugs. 13 (8): 568–580. PMC 3058503. PMID 20721828.
  2. ^ "Olesoxime". New Drugs Online Report. UK Medicines Information. Archived from the original on 2016-03-03.
  3. ^ Bordet T, Buisson B, Michaud M, Drouot C, Galéa P, Delaage P, et al. (August 2007). "Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis". The Journal of Pharmacology and Experimental Therapeutics. 322 (2): 709–720. doi:10.1124/jpet.107.123000. PMID 17496168. S2CID 17271734.
  4. ^ Clemens LE, Weber JJ, Wlodkowski TT, Yu-Taeger L, Michaud M, Calaminus C, et al. (December 2015). "Olesoxime suppresses calpain activation and mutant huntingtin fragmentation in the BACHD rat". Brain. 138 (Pt 12): 3632–3653. doi:10.1093/brain/awv290. PMID 26490331.
  5. ^ Weber JJ, Ortiz Rios MM, Riess O, Clemens LE, Nguyen HP (2016-01-01). "The calpain-suppressing effects of olesoxime in Huntington's disease". Rare Diseases. 4 (1): e1153778. doi:10.1080/21675511.2016.1153778. PMC 4838320. PMID 27141414.
  6. ^ "Trophos announces results of phase 3 study of olesoxime in Amyotrophic Lateral Sclerosis". Press Release. Trophos. 2011-12-13. Archived from the original on 2014-02-23.
  7. ^ "Trophos announces top-line results of pivotal trial of olesoxime in spinal muscular atrophy". Press Release. Trophos. 2014-03-10. Archived from the original on 2014-12-11.
  8. ^ Bertini E, Dessaud E, Mercuri E, Muntoni F, Kirschner J, Reid C, et al. (July 2017). "Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial". The Lancet. Neurology. 16 (7): 513–522. doi:10.1016/S1474-4422(17)30085-6. hdl:2434/501447. PMID 28460889. S2CID 5842023.
  9. ^ Taylor, Nick P. (2018-06-01). "Roche scraps €120M SMA drug after hitting 'many difficulties'". www.fiercebiotech.com. Retrieved 2018-06-07.

Further reading