WARNING: This product is for research use only, not for human or veterinary use.
Hodoodo CAT#: H406101
CAS#: 1133432-49-1 (R-isomer)
Description: GDC-0834 is a potent and selective inhibitor of Bruton's tyrosine kinase (BTK), investigated as a potential treatment for rheumatoid arthritis. In vitro metabolite identification studies in hepatocytes revealed predominant formation of an inactive metabolite (M1) via amide hydrolysis in human. GDC-0834 was shown to be a potent reversible inhibitor of six known Aldehyde oxidase (AO) substrates with IC50 values ranging from 0.86 to 1.87 μM. Additionally, in silico modeling studies suggest that GDC-0834 is capable of binding in the active site of AO with the amide bond of GDC-0834 near the molybdenum cofactor (MoCo), orientated in such a way to enable potential nucleophilic attack on the carbonyl of the amide bond by the hydroxyl of MoCo. Together, the in vitro and in silico results suggest the involvement of AO in the amide hydrolysis of GDC-0834.
Hodoodo Cat#: H406101
Name: GDC-0834
CAS#: 1133432-49-1 (R-isomer)
Chemical Formula: C33H36N6O3S
Exact Mass: 596.26
Molecular Weight: 596.750
Elemental Analysis: C, 66.42; H, 6.08; N, 14.08; O, 8.04; S, 5.37
Related CAS #: 1133432-49-1 (R-isomer) . 1133432-50-4 (S-isomer) 1133432-46-8 (racemic) 1133432-47-9 (racemic TFA)
Synonym: GDC0834; GDC-0834; GDC 0834.
IUPAC/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
InChi Key: CDOOFZZILLRUQH-GDLZYMKVSA-N
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
SMILES Code: 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
Appearance: Solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >5 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
More Info:
| Biological target: | GDC-0834 is a potent and selective BTK inhibitor. GDC-0834 inhibits BTK 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. |
| In vitro activity: | Allopurinol did not inhibit the metabolism of GDC-0834 and displayed an IC50 >50 μM. In DLC, inhibition of GDC-0834 metabolism and M1 formation was observed only with the CES inhibitor BNPP (IC50 = 15.6 μM); all other inhibitors, including loperamide, had IC50 >50 μM. Reference: Drug Metab Dispos. 2015 Jun;43(6):908-15. https://pubmed.ncbi.nlm.nih.gov/25845827/ |
| In vivo activity: | The treatment of BALB/c mice with GDC-0834 resulted in dose-dependent inhibition of pBTK-Tyr223. Animals dosed with 150 or 100 mg/kg GDC-0834 for 2 h showed complete inhibition of pBTK-Tyr223 levels in blood, with a mean inhibition of 97 and 96%, respectively. Individual animal plasma GDC-0834 concentrations from different time points and percentage of inhibition of pBTK-Tyr223 levels in blood were plotted to assess a PK/PD relationship (eq. 1). Reference: J Pharmacol Exp Ther. 2011 Jul;338(1):154-63. https://pubmed.ncbi.nlm.nih.gov/21521773/ |
| Solvent | Max Conc. mg/mL | Max Conc. mM | |
|---|---|---|---|
| Solubility | |||
| DMSO | 32.0 | 53.62 |
The following data is based on the product molecular weight 596.75 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass | 1 mg | 5 mg | 10 mg |
|---|---|---|---|
| 1 mM | 1.15 mL | 5.76 mL | 11.51 mL |
| 5 mM | 0.23 mL | 1.15 mL | 2.3 mL |
| 10 mM | 0.12 mL | 0.58 mL | 1.15 mL |
| 50 mM | 0.02 mL | 0.12 mL | 0.23 mL |
| Formulation protocol: | 1. Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CE, Barr JT, Jones JP, Halladay JS. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 2015 Jun;43(6):908-15. doi: 10.1124/dmd.114.061804. Epub 2015 Apr 6. PMID: 25845827; PMCID: PMC4429680. 2. 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 Jul;338(1):154-63. doi: 10.1124/jpet.111.181545. Epub 2011 Apr 26. PMID: 21521773. |
| In vitro protocol: | 1. Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CE, Barr JT, Jones JP, Halladay JS. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 2015 Jun;43(6):908-15. doi: 10.1124/dmd.114.061804. Epub 2015 Apr 6. PMID: 25845827; PMCID: PMC4429680. |
| In vivo protocol: | 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 Jul;338(1):154-63. doi: 10.1124/jpet.111.181545. Epub 2011 Apr 26. PMID: 21521773. |
1: Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CE, Barr JT, Jones JP, Halladay JS. A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos. 2015 Jun;43(6):908-15. doi: 10.1124/dmd.114.061804. Epub 2015 Apr 6. PubMed PMID: 25845827; PubMed Central PMCID: PMC4429680.
2: Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH, Liu L, Lubach JW, Macaluso J, Maciejewski P, Maurer B, Mitchell SA, Ortwine DF, Di Paolo J, Reif K, Scheerens H, Schmitt A, Sowell CG, Wang X, Wong H, Xiong JM, Xu J, Zhao Z, Currie KS. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett. 2015 Mar 15;25(6):1333-7. doi: 10.1016/j.bmcl.2015.01.032. Epub 2015 Feb 7. PubMed PMID: 25701252.
3: Akinleye A, Chen Y, Mukhi N, Song Y, Liu D. Ibrutinib and novel BTK inhibitors in clinical development. J Hematol Oncol. 2013 Aug 19;6:59. doi: 10.1186/1756-8722-6-59. Review. PubMed PMID: 23958373; PubMed Central PMCID: PMC3751776.
4: Robak T, Robak E. Tyrosine kinase inhibitors as potential drugs for B-cell lymphoid malignancies and autoimmune disorders. Expert Opin Investig Drugs. 2012 Jul;21(7):921-47. doi: 10.1517/13543784.2012.685650. Epub 2012 May 22. Review. PubMed PMID: 22612424.
5: Shin YG, Jones SA, Murakami SC, Liu L, Wong H, Buonarati MH, Hop CE. Validation and application of a liquid chromatography-tandem mass spectrometric method for the determination of GDC-0834 and its metabolite in human plasma using semi-automated 96-well protein precipitation. Biomed Chromatogr. 2012 Nov;26(11):1444-51. doi: 10.1002/bmc.2716. Epub 2012 Feb 7. PubMed PMID: 22311651.
6: Liu L, Halladay JS, Shin Y, Wong S, Coraggio M, La H, Baumgardner M, Le H, Gopaul S, Boggs J, Kuebler P, Davis JC Jr, Liao XC, Lubach JW, Deese A, Sowell CG, Currie KS, Young WB, Khojasteh SC, Hop CE, Wong H. Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor. Drug Metab Dispos. 2011 Oct;39(10):1840-9. doi: 10.1124/dmd.111.040840. Epub 2011 Jul 8. PubMed PMID: 21742900.
7: 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 Jul;338(1):154-63. doi: 10.1124/jpet.111.181545. Epub 2011 Apr 26. PubMed PMID: 21521773.
