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10mg | ||
25mg | ||
50mg | ||
100mg | ||
250mg |
Purity: ≥98%
BMS-751324 is a novel prodrug of BMS-582949 (also known as PS540446) which is a potent and highly selective p38 mitogen-activated protein kinase (p38 MAPK) inhibitor with IC50 of 13nM and is currently in phase II clinical trials for the treatment of rheumatoid arthritis. BMS-751324 was discovered in search for prodrugs to address the issue of pH-dependent solubility and exposure associated with BMS-582949, a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug. BMS-751324 has a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities. BMS-751324 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug BMS-582949 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of BMS-582949 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, BMS-751324 demonstrated similar efficacy to BMS-582949. Most importantly, it was shown in clinical studies that BMS-751324 was indeed effective in addressing the pH-dependent absorption issue associated with BMS-582949.
ln Vitro |
The alkaline phosphatase human placental ALP processes BMS-751324 (10 μM; 0-60 min), whereas the chemical enzyme factory does not [1].
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ln Vivo |
The drug BMS-751324 (1 mg/kg, 3 mg/kg; elbow; twice daily for one week) is used as a topological adjuvant for arthritis-related foot swelling. It is biotransformed in animals to produce BMS-582949 (suspension: 1 mg/kg-100 mg/kg, monkey: 10 or 30 mg/kg, 5 mL/kg methylcellulose suspension; and inhibits lipopolysaccharide-induced TNFα production [1]. Oral ; single dose) is administered to patients.
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References |
[1]. Liu C, et al. Discovery of 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo [1, 2-f][1, 2, 4] triazine-6-carboxamide (BMS-582949), a clinical p38α MAP kinase inhibitor for the treatment of inflammatory diseases[J]. Journal of medicinal chemistry, 2010, 53(18): 6629-6639.
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Molecular Formula |
C32H35N6O10P
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Molecular Weight |
694.628268480301
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CAS # |
948842-66-8
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SMILES |
P(=O)(O[H])(O[H])OC1C([H])=C([H])C(=C([H])C=1[H])C([H])([H])C(=O)OC([H])([H])OC(N(C([H])([H])C([H])([H])C([H])([H])[H])C(C1=C([H])N2C(=C1C([H])([H])[H])C(=NC([H])=N2)N([H])C1=C(C([H])([H])[H])C([H])=C([H])C(=C1[H])C(N([H])C1([H])C([H])([H])C1([H])[H])=O)=O)=O
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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 Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80: Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 :Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400  (Please use freshly prepared in vivo formulations for optimal results.) |
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Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
1 mM | 1.4396 mL | 7.1981 mL | 14.3962 mL | |
5 mM | 0.2879 mL | 1.4396 mL | 2.8792 mL | |
10 mM | 0.1440 mL | 0.7198 mL | 1.4396 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.