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Ro 61-8048 (Ro-618048) is a novel, high-affinity, oral, potent and selective kynurenine hydroxylase inhibitor (IC50 = 37 nM) with anti-dyskinesia activity. It can improve dystonia in a genetic model of paroxysmal dyskinesia and has the potential to be used for the treatment of dyskinesias. In addition, Ro 61-8048 may be useful to reduce neuronal loss in brain ischemia. Upon oral administration, Ro 61-8048 blocked rat and gerbil kynurenine 3-hydroxylase with ED50's in the 3-5 mumol/kg range in gerbil brain. In a microdialysis experiment in rats, Ro 61-8048 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 mumol/kg po led to a 7.5-fold increase in kynurenic acid outflow.
| ln Vitro |
The cerebral enzyme in gerbils is inhibited by a dose of 30 µmol/kg po (12.64 µg/kg Ro 61-8048, compound 16). This inhibition peaked after 2 hours (approximately 85% inhibition) and continued for up to 8 hours[1]. Ro 61-8048 (0.1-100 μM) significantly inhibits the formation of QUIN, indicating that kynurenine hydroxylase activity is necessary for QUIN neosynthesis in vitro[3].
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| ln Vivo |
In dtsz hamsters, Ro 61-8048 (50, 100, and 150 mg/kg ip) dramatically lessens the severity of dystonia without producing obvious central side effects[2]. In the striatum, cerebellum, and brainstem of mutant hamsters, Ro 61-8048 (100 mg/kg ip) causes an endogenous broad spectrum glutamate receptor antagonist kynurenic acid to increase two to three times[2].
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| Animal Protocol |
Animal/Disease Models: Male and female dtsz mutant Syrian golden hamsters[2].
Doses: 50, 100 and 150 mg /kg. Route of Administration: IP, one dose. Experimental Results: Dramatically decreased the individual maximum severity of dystonia reached at the end of the observation period of 3 h at doses of 50, 100 and 150 mg/kg ip. 100 and 150 mg/kg Dramatically diminished the severity, indicating a fast onset of action. A delayed onset of dystonic attacks was observed after treatment with 150 mg/kg but not after administration of 50 and 100 mg/kg. At lower doses of 10 and 25 mg/kg, the compound failed to exert any antidystonic effects. Caused a moderate sedation and hypolocomotion 5 to 70 min after administration of 100 and 150 mg/kg, while no central adverse effects were observable at a dose of 50 mg/kg or lower doses. |
| References |
[1]. S Röver, et al. Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase. J Med Chem. 1997 Dec 19;40(26):4378-85.
[2]. Melanie Hamann, et al. Effects of the kynurenine 3-hydroxylase inhibitor Ro 61-8048 after intrastriatal injections on the severity of dystonia in the dt sz mutant. Eur J Pharmacol. 2008 May 31;586(1-3):156-9. [3]. AlbertoChiarugi, et al. Quinolinic acid formation in immune-activated mice: studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(-3-nitrophenyl) thiazol-2yl]-benzenesulfonamide (Ro 61-8048), two potent and selective inhibitors of kynureni |
| Additional Infomation |
Ro 61-8048 is a C-nitro compound.
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| Molecular Formula |
C17H15N3O6S2
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| Molecular Weight |
421.45
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| Exact Mass |
421.04
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| CAS # |
199666-03-0
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| Related CAS # |
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| PubChem CID |
5282337
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
627.4±65.0 °C at 760 mmHg
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| Flash Point |
333.3±34.3 °C
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| Vapour Pressure |
0.0±1.8 mmHg at 25°C
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| Index of Refraction |
1.641
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| LogP |
3.38
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
638
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C1C([H])=C([H])C(=C(C=1[H])OC([H])([H])[H])OC([H])([H])[H])(N([H])C1=NC(=C([H])S1)C1C([H])=C([H])C([H])=C(C=1[H])[N+](=O)[O-])(=O)=O
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| InChi Key |
NDPBMCKQJOZAQX-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H15N3O6S2/c1-25-15-7-6-13(9-16(15)26-2)28(23,24)19-17-18-14(10-27-17)11-4-3-5-12(8-11)20(21)22/h3-10H,1-2H3,(H,18,19)
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| Chemical Name |
3,4-dimethoxy-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.93 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (5.93 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: 20 mg/mL (47.46 mM) in 50% PEG300 50% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3728 mL | 11.8638 mL | 23.7276 mL | |
| 5 mM | 0.4746 mL | 2.3728 mL | 4.7455 mL | |
| 10 mM | 0.2373 mL | 1.1864 mL | 2.3728 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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