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Purity: ≥98%
BMS-582949 (also known as PS540446) is a potent and highly selective p38 mitogen-activated protein kinase (p38 MAPK) inhibitor with IC50 of 13nM. It is presently undergoing phase II clinical trials for the treatment of rheumatoid arthritis. Inhibiting p38MAPK, a crucial component of the inflammatory pathways involved in atherothrombosis, may lessen inflammation within atherosclerotic plaques. Both p38 kinase activity and p38 activation are inhibited by the drug BMS-582949. By measuring p38's phosphorylation, BMS-582949 is found to inhibit p38 activation in cells. Treatment with BMS-582949 of cells in which p38 has been activated by LPS quickly reversed p38 activation, as demonstrated by loss of phosphorylation of p38.
| Targets |
p38α (IC50 = 13 nM)
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| ln Vitro |
BMS-582949 is discovered to prevent p38 activation in cells, as shown by p38's phosphorylation. As evidenced by the loss of phosphorylation of p38, BMS-582949 treatment of cells in which p38 has been activated by LPS quickly reversed p38 activation. Inhibiting both p38 kinase activity and p38 activation in cells, BMS-582949 is a dual action p38 kinase inhibitor. By changing the conformation of the activation loop, which is phosphorylated by upstream kinases, BMS-582949 inhibits the phosphorylation of p38 by upstream MKK[2]. This is done by causing the activation loop to take on a less accessible conformation.
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| ln Vivo |
BMS-582949 is cleared from mice at a rate of 4.4 mL/min/kg. The mouse AUC0-8 h for BMS-582949 is 75.5 μM•h at a 10 mg/kg oral dose. In mice and rats, BMS-582949 had oral bioavailability values of 90% and 60%, respectively[1].
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| Enzyme Assay |
BMS-582949 was discovered to be 190-fold selective against Raf and 450-fold selective over Jnk2, a MAP kinase involved in inflammation. Further proof of BMS-582949's mode of binding to p38R was provided by X-ray crystallographic studies.
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| Cell Assay |
BMS-582949 inhibits p38 kinase activity as well as p38 activation. When p38 is phosphorylated, BMS-582949 is found to inhibit p38 activation in cells. As evidenced by the loss of phosphorylation of p38, BMS-582949 treatment of cells in which p38 has been activated by LPS quickly reversed p38 activation.
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| Animal Protocol |
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| References |
| Molecular Formula |
C22H26N6O2
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| Molecular Weight |
406.48
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| Exact Mass |
406.21
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| Elemental Analysis |
C, 65.01; H, 6.45; N, 20.68; O, 7.87
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| CAS # |
623152-17-0
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| Related CAS # |
BMS-582949 hydrochloride;912806-16-7
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| Appearance |
Solid powder
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| SMILES |
CCCNC(=O)C1=CN2C(=C1C)C(=NC=N2)NC3=C(C=CC(=C3)C(=O)NC4CC4)C
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| InChi Key |
GDTQLZHHDRRBEB-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H26N6O2/c1-4-9-23-22(30)17-11-28-19(14(17)3)20(24-12-25-28)27-18-10-15(6-5-13(18)2)21(29)26-16-7-8-16/h5-6,10-12,16H,4,7-9H2,1-3H3,(H,23,30)(H,26,29)(H,24,25,27)
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| Chemical Name |
4-[5-(cyclopropylcarbamoyl)-2-methylanilino]-5-methyl-N-propylpyrrolo[2,1-f][1,2,4]triazine-6-carboxamide;hydrochloride
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| Synonyms |
PS540446; BMS-582949; BMS 582949; PS-540446; PS 540446; BMS582949; BMS582949 free base
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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) |
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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.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4601 mL | 12.3007 mL | 24.6015 mL | |
| 5 mM | 0.4920 mL | 2.4601 mL | 4.9203 mL | |
| 10 mM | 0.2460 mL | 1.2301 mL | 2.4601 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00570752 | Completed | Other: Placebo Drug: BMS-582949 |
Vascular Diseases | Bristol-Myers Squibb | December 2008 | Phase 2 |
| NCT00605735 | Completed | Drug: BMS-582949 Drug: Placebo |
Rheumatoid Arthritis, NOS | Bristol-Myers Squibb | March 2008 | Phase 2 |
| NCT00399906 | Completed | Drug: BMS-582949 Drug: Placebo |
Psoriasis | Bristol-Myers Squibb | August 2007 | Phase 2 |
| NCT00162292 | Completed | Drug: BMS-582949 and Methotrexate |
Rheumatoid Arthritis | Bristol-Myers Squibb | November 2005 | Phase 1 |
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