GDC-0834 |
| رقم الكتالوجGC11995 |
GDC-0834 هو S-enantiomer لـ GDC-0834.
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 1133432-50-4
Sample solution is provided at 25 µL, 10mM.
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GDC-0834 is a potent and selective Bruton's tyrosine kinase (Btk) inhibitor, The IC50 values in biochemical and cellular assays is 5.9 and 6.4 nM. The in vivo IC50 values in mouse and rat are 1.1 and 5.6 μM, respectively [1]. B cell antigen receptor (BCR) stimulation phosphorylated and activated Btk. Btk gene defects result in a disease named as X-linked agammaglobulinemia which profoundly decreased mature B cells due to a block in B cell development [2].
In vivo: In a rat collagen-induced arthritis (CIA) model, administration of GDC-0834 (30-100 mg/kg) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology [1].In PXB chimeric mice with humanized liver, GDC-0834 exhibited low clearance. in most samples from the cohorts dosed orally at 35 and 105 mg GDC-0834, plasma concentrations of GDC-0834 in humans were below the limit of quantitation (<1 ng/ml). High interest in a BTK inhibitor for clinical evaluation and uncertainty in human pharmacokinetic prediction prompted an investigational new drug strategy, in which GDC-0834 was rapidly advanced to a single-dose human clinical trial [3].
References:
[1]. Liu L, Di Paolo J, Barbosa J, et al. Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy[J]. Journal of Pharmacology and Experimental Therapeutics, 2011, 338(1): 154-163.
[2]. Takata M, Kurosaki T. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2[J]. The Journal of experimental medicine, 1996, 184(1): 31-40.
[3]. Liu L, Halladay J S, Shin Y, et al. Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor[J]. Drug Metabolism and Disposition, 2011, 39(10): 1840-1849.
| Kinase experiment [1]: | |
|
Enzyme Inhibition |
Btk activity was quantified by determining phosphorylation of an exogenous peptide product in a Lanthascreen assay. In a final reaction volume of 25 μl, Btk [human, full-length, C-terminal V5–6× His, expressed in Sf9 cells; 0.075 ng/25 μl reaction) was incubated with 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM MnCl2, 2 mM dithiothreitol, 0.2 mM NaVO4, 0.01% casein, 0.01% Triton X-100, 2.5% glycerol, and 0.4 μM fluorescein poly-Glu/Ala/Tyr. The reaction was initiated by the addition of ATP to 25 μM (Km of ATP). After incubation for 60 min at room temperature, the reaction was stopped by the addition of a final concentration of 2 nM Tb-PY20 detection antibody in 60 mM EDTA for 30 min at room temperature. Detection was determined on a PerkinElmer Envision with 340-nM excitation and emission at 495 and 520 nm. |
| Cell experiment [1]: | |
|
Cell lines |
Rat splenocytes |
|
Preparation method |
This compound is soluble in DMSO. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
|
Reacting condition |
Five hundred microliters of cell suspension (1×107 cells/ml) was incubated with GDC-0834 for 1 h at 37°C, followed by stimulation with 3 μg/ml αIgM (final concentration) for 3 min. |
|
Applications |
In the rat splenocytes, GDC-0834 suppressed pBTK activity with an IC50 value of 6.4 ± 1.6 nM with Hill slope value of 0.76 ± 0.19. |
| Animal experiment [1]: | |
|
Animal models |
Female arthritis Lewis rats |
|
Dosage form |
Oral dosing of GDC-0834 [vehicle, 1, 3, 10, 30, and 100 mg/kg b.i.d. (twice daily) at 12-h intervals, vehicle, 10, 30, 100 mg/kg once daily (QD) at 24-h intervals, and 100 mg/kg every other day (Q2D) at 48 intervals] was initiated on day 0 of the study and continued through day 16. |
|
Application |
Treatment with GDC-0834 resulted in a significant reduction of the area under the ankle diameter-time curve in arthritis rat model. |
|
Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
|
References: [1]. Liu L, Di Paolo J, Barbosa J, Rong H, Reif K, Wong H. Antiarthritis effect of a novel Bruton’s tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther. 2011;338(1):154–163. | |
| Cas No. | 1133432-50-4 | SDF | |
| Chemical Name | N-[3-[6-[4-[(2S)-1,4-dimethyl-3-oxopiperazin-2-yl]anilino]-4-methyl-5-oxopyrazin-2-yl]-2-methylphenyl]-4,5,6,7-tetrahydro-1-benzothiophene-2-carboxamide | ||
| Canonical SMILES | CC1=C(C=CC=C1NC(=O)C2=CC3=C(S2)CCCC3)C4=CN(C(=O)C(=N4)NC5=CC=C(C=C5)C6C(=O)N(CCN6C)C)C | ||
| Formula | C33H36N6O3S | M.Wt | 596.74 |
| الذوبان | DMSO : 100 mg/mL (167.58 mM; Need ultrasonic) | Storage | Store at -20° C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 1.6758 mL | 8.3789 mL | 16.7577 mL |
| 5 mM | 0.3352 mL | 1.6758 mL | 3.3515 mL |
| 10 mM | 0.1676 mL | 0.8379 mL | 1.6758 mL |
Step 1: Enter information below (Recommended: An additional animal making an allowance for loss during the experiment)
g
μL
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Calculation results:
Working concentration: mg/ml;
Method for preparing DMSO master liquid: mg drug pre-dissolved in μL DMSO ( Master liquid 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 master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.
Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.
Note: 1. Please make sure the liquid is clear before adding the next solvent.
2. Be sure to add the solvent(s) in order. You must ensure that the solution obtained, in the previous addition, is a clear solution before proceeding to add the next solvent. Physical methods such as vortex, ultrasound or hot water bath can be used to aid dissolving.
3. All of the above co-solvents are available for purchase on the GlpBio website.
Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Average Rating: 5 (Based on Reviews and 32 reference(s) in Google Scholar.)
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