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5mg |
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10mg |
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Purity: ≥98%
GDC-0834 (R-enantiomer) is a novel, potent and selective BTK inhibitor with an in vitro IC50 of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC50 of 1.1 and 5.6 μM in mouse and rat, respectively. Bruton's tyrosine kinase (BTK) plays a critical role in the development, differentiation, and proliferation of B-lineage cells, making it an attractive target for the treatment of rheumatoid arthritis. GDC-0834 inhibited BTK with an in vitro IC(50) of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and in vivo IC(50) of 1.1 and 5.6 μM in mouse and rat, respectively. Administration of GDC-0834 (30-100 mg/kg) in a rat collagen-induced arthritis (CIA) model resulted in a dose-dependent decrease of ankle swelling and reduction of morphologic pathology. An integrated disease progression pharmacokinetic/pharmacodynamic model where efficacy is driven by pBTK inhibition was fit to ankle-diameter time-course data. This model incorporated a transit model to characterize nondrug-related decreases in ankle swelling occurring at later stages of disease progression in CIA rats. The time course of ankle swelling in vehicle animals was described well by the base model. Simultaneous fitting of data from vehicle- and GDC-0834-treated groups showed that overall 73% inhibition of pBTK was needed to decrease the rate constant describing the ankle swelling increase (k(in)) by half. These findings suggest a high degree of pBTK inhibition is required for maximal activity of the pathway on inflammatory arthritis in rats.
ln Vitro |
With an IC50 value of 5.9±1.1 nM and a Hill slope value of -0.84±0.07 (mean±SE), GDC-0834 inhibits BTK kinase activity [1]. With IC50 values ranging from 0.86 to 1.87 μM, GDC-0834 was demonstrated to be a strong and reversible inhibitor of six recognized aldehyde oxidase (AO) substrates[2].
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ln Vivo |
GDC-0834 treatment of BALB/c mice led to pBTK-Tyr223 inhibition in a dose-dependent manner. The blood levels of pBTK-Tyr223 were completely inhibited in animals given 150 or 100 mg/kg GDC-0834 for two hours, with average inhibition rates of 97% and 96%, respectively. GDC-0834 suppressed pBTK-Tyr223 in rat blood in a dose-dependent manner in a research on CIA rats. Rats' estimated IC50 for pBTK-Tyr223 inhibition is 5.6±1.6 μM, with a mean±standard error of 0.51±0.087 [1].
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References |
[1]. Liu L, 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
[2]. Sodhi JK, et al. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 2015 Jun;43(6):908-15 |
Molecular Formula |
C33H36N6O3S
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Molecular Weight |
596.742345809937
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CAS # |
1133432-49-1
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SMILES |
O=C(C1=CC(CCCC2)=C2S1)NC3=CC=CC(C(N=C4NC5=CC=C([C@H]6N(C)CCN(C)C6=O)C=C5)=CN(C)C4=O)=C3C
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InChi Key |
CDOOFZZILLRUQH-GDLZYMKVSA-N
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InChi Code |
InChI=1S/C33H36N6O3S/c1-20-24(9-7-10-25(20)36-31(40)28-18-22-8-5-6-11-27(22)43-28)26-19-39(4)33(42)30(35-26)34-23-14-12-21(13-15-23)29-32(41)38(3)17-16-37(29)2/h7,9-10,12-15,18-19,29H,5-6,8,11,16-17H2,1-4H3,(H,34,35)(H,36,40)/t29-/m1/s1
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Chemical Name |
(R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
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Synonyms |
GDC0834; GDC-0834; GDC 0834.
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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 : ≥ 32 mg/mL (~53.62 mM)
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Preparing Stock Solutions | 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 |
*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.
Proteomic correlation profiling revealed that aldehyde oxidase (AO/ADO) is an enzyme present in cytosolic fractions containing the hydrolytic enzyme activity involved in the metabolism of GDC-0834.Drug Metab Dispos.2015 Jun;43(6):908-15. th> |
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Homology model for aldehyde oxidase (AO) using the human sequence and the mouse crystal structure (PDB ID 3ZYV). Formation of M1 after incubation of GDC-0834 (0.8µM) in (A) fresh whole blood and (B) plasma in human (○), rat (), mouse (▲), dog (♦), and monkey (●). td> |
IC50curves for the inhibition by GDC-0834 (0–50 or 0–100μM) of AO-mediated metabolism of AO probe substrates in human liver cytosol (A) carbazeran (formation of 4-hydroxycarbazeran), (B) DACA (formation of DACA-9(10H)-acridone), (C)O6-benzylguanine (formation of 8-oxobenzylguanine), (D) phthalazine (formation of phthalazinone), (E) zaleplon (formation of 5-oxozaleplon), and (F) zoniporide (formation of 2-oxozoniporide).Drug Metab Dispos.2015 Jun;43(6):908-15. td> |