"目录号: HY-14796
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TRO 19622 是一种靶向线粒体的神经保护性试剂，促进细胞存活，EC50为 3.2±0.2 μM。
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生物活性
Description
TRO 19622 is amitochondrial-targeted neuroprotective compound with mean EC50value for increasing cell survival is 3.2±0.2 μM.
IC50& Target
Mitochondrial[1]
In Vitro
Exposure to TRO19622 (ranging from 0.1 to 10 μM) at 1 h after plating significantly protects primary embryonic rat spinal MNs (that had been cultured for 3 days without brain-derived, ciliary and glia-derived neurotrophic factors) from cell death. At a concentration of 10 μM, TRO19622 (Olesoxime) maintains survival of 74±10% of the neurons supported by a combination of neurotrophic factors (brain-derived, ciliary and glia-derived neurotrophic factors). The mean EC50in this assay is 3.2±0.2 μM. In addition to preserving MN cell bodies, TRO19622 also promotes the outgrowth of neurites. At a concentration of 1 μM, which increases cell survival by only 38%, TRO19622 increases overall neurite outgrowth per cell by 54%[1]. TRO 19622 belongs to a new family of cholesterol-oximes identified for its survival-promoting activity on purified motor neurons deprived of neurotrophic factors. TRO 19622 targets proteins of the outer mitochondrial membrane, concentrates at the mitochondria and prevents permeability transition pore opening mediated by, among other things, oxidative stress[2].
In Vivo
Daily administration of TRO19622 (3 or 30 mg/kg sc) to adult mice for more than 2 months is well tolerated without toxicity or adverse effects[1]. When animals are treated orally for 5 days following the lesion, TRO19622 increases motor neuron cell body survival in a dose-dependent manner with significant rescue at the highest dose of 100 mg/kg. At this dose, motor neuron survival is 29 ±2% (n=18) corresponding to a 42% increase in survival compared with vehicle-treated animals[3]. Paclitaxel-treated rats that receive prophylactic treatment with 3 mg/kg/d or 30 mg/kg/d TRO19622 (Olesoxime) have 239±17.6 and 247±14.4 IENFs per cm, respectively. For both doses, the decreases are significantly less than the 46% decrease seen in the Paclitaxel-treated rats administered vehicle. However, both doses produce decreases (25% and 22%) that are significantly different relative to the na?ve control group[4].
Clinical Trial
NCT01808885
Hoffmann-La Roche-Hôpital de la Timone-SGS S.A.-STRAGEN Services
Relapsing Remitting Multiple Sclerosis
April 2013
Phase 1
NCT02835976
Hoffmann-La Roche-Trophos SA
Healthy Volunteer
July 2014
Phase 1
NCT02628743
Hoffmann-La Roche
Muscular Atrophy, Spinal
January 20, 2016
Phase 2
NCT01302600
Hoffmann-La Roche-Association Française contre les Myopathies (AFM), Paris
Spinal Muscular Atrophy Type II-Spinal Muscular Atrophy Type III Non Ambulant
November 2010
Phase 2
NCT00868166
Trophos-European Commission
Amyotrophic Lateral Sclerosis
April 2009
Phase 2-Phase 3
NCT00876538
Hoffmann-La Roche
Chemotherapy-Induced Peripheral Neuropathy
March 2009
Phase 2
NCT00666016
Hoffmann-La Roche
Non-Alcoholic Steatohepatitis (NASH)
April 2008
Phase 2
NCT01285583
Hoffmann-La Roche
Amyotrophic Lateral Sclerosis
October 2010
Phase 2-Phase 3
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References
[1].Martin LJ, et al. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis. IDrugs. 2010 Aug;13(8):568-80.
[2].Bordet T, et al. Olesoxime (TRO19622): A Novel Mitochondrial-Targeted Neuroprotective Compound. Pharmaceuticals (Basel). 2010 Jan 28;3(2):345-368.
[3].Bordet T, et al. Identification and characterization of cholest-4-en-3-one, oxime (TRO19622), a novel drug candidate for amyotrophic lateral sclerosis. J Pharmacol Exp Ther. 2007 Aug;322(2):709-20.
[4].Xiao WH, et al. 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. 2009 Dec 15;147(1-3):202-9.