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LXE408 is a novel, potent, orally bioactive and non-competitive inhibitor of kinetoplastid-selective proteasome with an IC50 of 0.04 μM for L. donovani proteasome and an EC50 of 0.04 μM for L. donovani. LXE408 has the potential for treating visceral leishmaniasis.
ln Vitro |
LXE408 (compound 1) has the ability to form a ternary complex with the proteasome in order to occupy the pocket. LXE408 has a limited propensity to cross the blood-brain barrier (mouse brain/plasma AUC ratio = 0.03) and no inhibitory impact on hERG channels (IC50>30 μM) in manual patch clamp studies [1].
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ln Vivo |
LXE408 (Compound 1; 0.3-10 mg/kg; oral; twice daily for 8 days) substantially lowers parasite burden in the liver in a dose-dependent manner [1]. LXE408 (1, 3, 10, 20 mg/kg; oral; twice daily; for 10 days) can effectively heal skin lesions caused by parasites near the tail base of BALB/c mice infected with Le. major [1]. LXE408 (5 mg/kg IV and 20 mg/kg PO) showed a T1/2 of 3.3 hours in mice. LXE408 (3 mg/kg IV and 10 mg/kg PO) had a T1/2 of 3.8 hours, a CL of 2.1 mL/min·kg, and a Vss of 0.53 L/kg in male Sprague-Dawley rats[1]. LXE408 (0.3 mg/kg IV and 1.0 mg/kg PO) showed a T1/2 of 3.8 hours in male beagle dogs. LXE408 (0.3 mg/kg IV and 10 mg/kg PO) had a T1/2 of 9.7 hours in male cynomolgus monkeys [1].
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Animal Protocol |
Animal/Disease Models: Female balb/c (Bagg ALBino) mouse (6-8 weeks old) infected with Lactobacillus donovani [1]
Doses: 0.3, 1, 3, 10 mg/kg Route of Administration: Oral; twice (two times) daily for 8 days Experimental Results: Parasite burden in the liver was diminished by 95% and >99.84% at doses of 1 mg/kg and 10 mg/kg. Animal/Disease Models: balb/c (Bagg ALBino) mouse [1] Doses: 5 mg/kg IV and 20 mg/kg PO (pharmacokinetic/PK/PK analysis) Route of Administration: IV or PO Experimental Results: T1/2 was 3.3 hrs (hrs (hours)), CL was 2.3 mL /min •kg, the Vss of mice is 0.63L/kg. |
References |
Molecular Formula |
C23H18FN7O2
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Molecular Weight |
443.4331
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Exact Mass |
443.15
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CAS # |
1799330-15-6
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PubChem CID |
118162630
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Appearance |
Off-white to light yellow solid powder
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LogP |
3.2
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Hydrogen Bond Donor Count |
1
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Hydrogen Bond Acceptor Count |
8
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Rotatable Bond Count |
4
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Heavy Atom Count |
33
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Complexity |
702
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Defined Atom Stereocenter Count |
0
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SMILES |
FC1C([H])=C([H])C(=C([H])C=1C1N=C2N=C([H])C(C3=C(C([H])([H])[H])C([H])=C([H])C([H])=N3)=C([H])N2N=1)N([H])C(C1=C(C([H])([H])[H])N=C(C([H])([H])[H])O1)=O
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InChi Key |
GNVVPYCWVLCWKV-UHFFFAOYSA-N
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InChi Code |
InChI=1S/C23H18FN7O2/c1-12-5-4-8-25-19(12)15-10-26-23-29-21(30-31(23)11-15)17-9-16(6-7-18(17)24)28-22(32)20-13(2)27-14(3)33-20/h4-11H,1-3H3,(H,28,32)
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Chemical Name |
N-[4-fluoro-3-[6-(3-methylpyridin-2-yl)-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl]phenyl]-2,4-dimethyl-1,3-oxazole-5-carboxamide
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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 |
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) |
DMSO : ~16.67 mg/mL (~37.59 mM)
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Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 0.62 mg/mL (1.40 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 6.2 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: ≥ 0.62 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 6.2 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: ≥ 0.62 mg/mL (1.40 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 2.2551 mL | 11.2757 mL | 22.5515 mL | |
5 mM | 0.4510 mL | 2.2551 mL | 4.5103 mL | |
10 mM | 0.2255 mL | 1.1276 mL | 2.2551 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.