Jump to content

Olesoxime

From Wikipedia, the free encyclopedia
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

[edit]

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

[edit]
  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 20721828.568-580&rft.date=2010-08&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058503#id-name=PMC&rft_id=info:pmid/20721828&rft.aulast=Martin&rft.aufirst=LJ&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058503&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  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 17271734.709-720&rft.date=2007-08&rft_id=https://api.semanticscholar.org/CorpusID:17271734#id-name=S2CID&rft_id=info:pmid/17496168&rft_id=info:doi/10.1124/jpet.107.123000&rft.aulast=Bordet&rft.aufirst=T&rft.au=Buisson, B&rft.au=Michaud, M&rft.au=Drouot, C&rft.au=Galéa, P&rft.au=Delaage, P&rft.au=Akentieva, NP&rft.au=Evers, AS&rft.au=Covey, DF&rft.au=Ostuni, MA&rft.au=Lacapère, JJ&rft.au=Massaad, C&rft.au=Schumacher, M&rft.au=Steidl, EM&rft.au=Maux, D&rft.au=Delaage, M&rft.au=Henderson, CE&rft.au=Pruss, RM&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  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 26490331.3632-3653&rft.date=2015-12&rft_id=info:doi/10.1093/brain/awv290&rft_id=info:pmid/26490331&rft.aulast=Clemens&rft.aufirst=LE&rft.au=Weber, JJ&rft.au=Wlodkowski, TT&rft.au=Yu-Taeger, L&rft.au=Michaud, M&rft.au=Calaminus, C&rft.au=Eckert, SH&rft.au=Gaca, J&rft.au=Weiss, A&rft.au=Magg, JC&rft.au=Jansson, EK&rft.au=Eckert, GP&rft.au=Pichler, BJ&rft.au=Bordet, T&rft.au=Pruss, RM&rft.au=Riess, O&rft.au=Nguyen, HP&rft_id=https://doi.org/10.1093%2Fbrain%2Fawv290&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  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 5842023.513-522&rft.date=2017-07&rft_id=info:hdl/2434/501447&rft_id=https://api.semanticscholar.org/CorpusID:5842023#id-name=S2CID&rft_id=info:pmid/28460889&rft_id=info:doi/10.1016/S1474-4422(17)30085-6&rft.aulast=Bertini&rft.aufirst=E&rft.au=Dessaud, E&rft.au=Mercuri, E&rft.au=Muntoni, F&rft.au=Kirschner, J&rft.au=Reid, C&rft.au=Lusakowska, A&rft.au=Comi, GP&rft.au=Cuisset, JM&rft.au=Abitbol, JL&rft.au=Scherrer, B&rft.au=Ducray, PS&rft.au=Buchbjerg, J&rft.au=Vianna, E&rft.au=van der Pol, WL&rft.au=Vuillerot, C&rft.au=Blaettler, T&rft.au=Fontoura, P&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  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

[edit]
  • Rovini A, Carré M, Bordet T, Pruss RM, Braguer D (September 2010). "Olesoxime prevents microtubule-targeting drug neurotoxicity: selective preservation of EB comets in differentiated neuronal cells". Biochemical Pharmacology. 80 (6): 884–894. doi:10.1016/j.bcp.2010.04.018. PMID 20417191.884-894&rft.date=2010-09&rft_id=info:doi/10.1016/j.bcp.2010.04.018&rft_id=info:pmid/20417191&rft.aulast=Rovini&rft.aufirst=A&rft.au=Carré, M&rft.au=Bordet, T&rft.au=Pruss, RM&rft.au=Braguer, D&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  • Xiao WH, Zheng FY, Bennett GJ, Bordet T, Pruss RM (December 2009). "Olesoxime (cholest-4-en-3-one, oxime): analgesic and neuroprotective effects in a rat model of painful peripheral neuropathy produced by the chemotherapeutic agent, paclitaxel". Pain. 147 (1–3): 202–209. doi:10.1016/j.pain.2009.09.006. PMC 2787910. PMID 19833436.1–3&rft.pages=202-209&rft.date=2009-12&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787910#id-name=PMC&rft_id=info:pmid/19833436&rft_id=info:doi/10.1016/j.pain.2009.09.006&rft.aulast=Xiao&rft.aufirst=WH&rft.au=Zheng, FY&rft.au=Bennett, GJ&rft.au=Bordet, T&rft.au=Pruss, RM&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787910&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
  • Bordet T, Buisson B, Michaud M, Abitbol JL, Marchand F, Grist J, et al. (August 2008). "Specific antinociceptive activity of cholest-4-en-3-one, oxime (TRO19622) in experimental models of painful diabetic and chemotherapy-induced neuropathy". The Journal of Pharmacology and Experimental Therapeutics. 326 (2): 623–632. doi:10.1124/jpet.108.139410. PMID 18492948. S2CID 33726393.623-632&rft.date=2008-08&rft_id=https://api.semanticscholar.org/CorpusID:33726393#id-name=S2CID&rft_id=info:pmid/18492948&rft_id=info:doi/10.1124/jpet.108.139410&rft.aulast=Bordet&rft.aufirst=T&rft.au=Buisson, B&rft.au=Michaud, M&rft.au=Abitbol, JL&rft.au=Marchand, F&rft.au=Grist, J&rft.au=Andriambeloson, E&rft.au=Malcangio, M&rft.au=Pruss, RM&rfr_id=info:sid/en.wikipedia.org:Olesoxime" class="Z3988">
[edit]
Retrieved from "https://en.wikipedia.org/w/index.php?title=Olesoxime&oldid=1215135875"