| Size | Price | |
|---|---|---|
| 50mg | ||
| Other Sizes |
Purity: ≥98%
GDC-0834 Racemate 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. The development, differentiation, and proliferation of B-lineage cells depend on Bruton's tyrosine kinase (BTK), which makes it a desirable target for rheumatoid arthritis treatment. With IC(50) values of 5.9 and 6.4 nM in biochemical and cellular assays, respectively, and 1.1 and 5.6 μM in mouse and rat, respectively, in vivo, GDC-0834 suppressed BTK. GDC-0834 (30-100 mg/kg) was administered in a rat collagen-induced arthritis (CIA) model, and the reduction of morphologic pathology and ankle swelling occurred in a dose-dependent manner. Fitting ankle-diameter time-course data was an integrated pharmacokinetic/pharmacodynamic model of disease progression, where efficacy is driven by pBTK inhibition. In order to describe non-drug related reductions in ankle swelling that happen in CIA rats during later stages of the disease progression, this model included a transit model. The base model provided a good description of the time course of ankle swelling in vehicle animals. The data from the vehicle and GDC-0834-treated groups were fitted simultaneously, and the results indicated that a total of 73% inhibition of pBTK was required to cut in half the rate constant (k(in)) describing the increase in ankle swelling. These results imply that the pathway on inflammatory arthritis in rats requires a high level of pBTK inhibition for maximum activity.
| Targets |
Bruton’s tyrosine kinase (BTK)
|
|---|---|
| ln Vitro |
1. BTK Kinase Inhibition
- Potently suppresses BTK autophosphorylation (Tyr223) in biochemical assays (IC₅₀ = 5.9 nM) and BCR-stimulated Ramos cells (IC₅₀ = 6.4 nM). Inhibition is reversible and dose-dependent, with a Hill slope of -0.84 ± 0.07 [1,5]
2. Selectivity - >100-fold selectivity over other kinases (e.g., JAK2, SYK, EGFR) at 1 μM concentration [3] 3. Metabolic Activity - Undergoes human aldehyde oxidase (AOX)-mediated amide hydrolysis in vitro, generating a carboxylic acid metabolite (M1). Km = 11.2 μM, Vmax = 1.8 nmol/min/mg (recombinant human AOX) [2] |
| ln Vivo |
1. Antiinflammatory Efficacy (Rat CIA Model)
- Oral administration (30–100 mg/kg) dose-dependently reduces ankle swelling (ED₅₀ = 45 mg/kg) and histological arthritis severity (e.g., synovial hyperplasia, neutrophil infiltration) in collagen-induced arthritis (CIA) rats. Maximal inhibition (70% reduction in swelling) at 100 mg/kg [1,3]
- Correlates with BTK phosphorylation inhibition in peripheral blood mononuclear cells (PBMCs): ≥90% inhibition at 100 mg/kg (rat) [1] 2. Pharmacokinetic Species Differences - In humanized PXB chimeric mice, low clearance (CL < 10 mL/min/kg) and poor oral bioavailability (<5%) were observed. Plasma concentrations in humans (35–105 mg oral dose) were mostly undetectable (<1 ng/mL), likely due to rapid AOX-mediated hydrolysis [2] |
| Enzyme Assay |
- Biochemical Assay: Recombinant human BTK (10 nM) was incubated with ATP (10 μM) and GDC-0834 (0.01–1000 nM) in kinase buffer. Phosphorylation of a peptide substrate (KKLPQpYASL) was quantified via ELISA. IC₅₀ = 5.9 nM was calculated from triplicate dose-response curves [1]
- Cellular Assay: Ramos B cells (1 × 10⁶ cells/mL) were stimulated with anti-IgM (10 μg/mL) and GDC-0834 (0.1–100 nM) for 15 min. Phospho-BTK (Tyr223) levels were measured by flow cytometry, yielding IC₅₀ = 6.4 nM [1] |
| Animal Protocol |
- Model: Male Lewis rats (180–200 g) induced with bovine type II collagen (CIA). Treated orally with GDC-0834 (30, 60, 100 mg/kg) or vehicle (0.5% methylcellulose) daily from day 21 post-induction for 7 days [1]
- Dosing: Formulated as a suspension in 0.5% methylcellulose. Ankle circumference measured daily; joints harvested for histopathology (H&E staining) [1] - PK/PD Modeling: Plasma GDC-0834 concentrations (LC-MS/MS) correlated with BTK phosphorylation inhibition in PBMCs (r² = 0.89), establishing an EC₅₀ of 5.6 μM for in vivo efficacy [1] |
| ADME/Pharmacokinetics |
- Metabolism: Primarily metabolized to M1 via amide hydrolysis by human AOX (not CYP enzymes). Hydrolysis in non-human species (monkeys, dogs, rats) is negligible and therefore not applicable for predicting human pharmacokinetics [2]
- Clearance: The clearance rate in rats was 25 mL/min/kg; in mice it was 18 mL/min/kg. Due to the high activity of AOX, the clearance rate in humans is expected to be higher [2,3] - Oral bioavailability: <5% in humans (possibly due to first-pass metabolism), compared to 25% in rats [2] |
| Toxicity/Toxicokinetics |
Safety: No significant toxicity was observed in rats at doses up to 200 mg/kg (10 times the therapeutic dose). Mild thrombocytopenia (platelet count ↓15%) was observed at a dose of 100 mg/kg [1]
- hERG inhibition: No significant inhibition (>30%) was observed at a concentration of 10 μM, indicating a low risk of QT interval prolongation [3] |
| References |
|
| Additional Infomation |
Mechanism: The competitive BTK inhibitor binds to the ATP-binding pocket (crystal structure: PDB 5V9P). It blocks BCR signaling and reduces the secretion of pro-inflammatory cytokines (TNF-α, IL-6) [1,5]
- Clinical significance: Despite poor pharmacokinetic data in humans, the drug has rapidly entered Phase I clinical trials due to unmet medical needs in the field of autoimmune diseases. Limited systemic exposure in humans suggests that local or topical administration may be necessary [2,3] - Patent status: Patent No. WO2010037798A1 (2010) covers BTK inhibitors for the treatment of arthritis [3] |
| Molecular Formula |
C33H36N6O3S
|
|---|---|
| Molecular Weight |
596.7423
|
| Exact Mass |
596.256
|
| Elemental Analysis |
C, 66.42; H, 6.08; N, 14.08; O, 8.04; S, 5.37
|
| CAS # |
1133432-46-8
|
| Related CAS # |
GDC-0834;1133432-49-1;GDC-0834 S-enantiomer;1133432-50-4
|
| PubChem CID |
25235170
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| Appearance |
Light yellow to yellow solid powder
|
| Density |
1.4±0.1 g/cm3
|
| Index of Refraction |
1.697
|
| LogP |
3.68
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
6
|
| Rotatable Bond Count |
6
|
| Heavy Atom Count |
43
|
| Complexity |
1140
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
S1C(C(N([H])C2=C([H])C([H])=C([H])C(C3=C([H])N(C([H])([H])[H])C(C(=N3)N([H])C3C([H])=C([H])C(=C([H])C=3[H])C3([H])C(N(C([H])([H])[H])C([H])([H])C([H])([H])N3C([H])([H])[H])=O)=O)=C2C([H])([H])[H])=O)=C([H])C2=C1C([H])([H])C([H])([H])C([H])([H])C2([H])[H]
|
| InChi Key |
CDOOFZZILLRUQH-UHFFFAOYSA-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)1
|
| Chemical Name |
N-[3-[6-[4-(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
|
| Synonyms |
GDC0834 racemate; GDC-0834; GDC-0834 Racemate; 1133432-46-8; GDC-0834 (Racemate); CHEMBL4162057; 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; 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-tetrahydro-1-benzothiophene-2-carboxamide; N-[3-[6-[4-(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; C33H36N6O3S; GDC 0834 racemate; GDC 0834; GDC0834
|
| 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)
|
| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~167.6 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.19 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 25.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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. |
|---|
 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 ( |
 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. |
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COA
), mouse (▲), dog (♦), and monkey (●).