GSK 525762A Chemical Properties

Melting point:

>132°C (dec.)

Density 

1.35

storage temp. 

2-8°C

solubility 

Soluble in DMSO (up to at least 25 mg/ml) or in Ethanol (up to at least 25 mg/ml)

form 

powder

pka

15.71±0.46(Predicted)

color 

white to beige

optical activity

[α]/D +80 to +90°, c = 0.3 in methanol

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months.

GSK 525762A Usage And Synthesis

Description

The bromodomain and extra terminal domain (BET) family of proteins, including BRD2, BRD3, and BRD4, affect inflammatory gene expression by controlling the assembly of histone acetylation-dependent chromatin complexes. I-BET762 is a synthetic compound which interacts with BET proteins with high-affinity (K_d = 32.5-42.5 nM). It blocks binding of BET proteins with acetylated histones, disrupting the formation of chromatin complexes involved in the expression of specific inflammatory genes in activated macrophages. Through these actions, I-BET762 provides protection against bacteria-induced sepsis and lipopolysaccharide-triggered endotoxic shock.

Uses

GSK 525762A, is a BET Bromodomain Inhibitor, which is now in clinical development. BET bromodomains have emerged as promising drug targets for treatment of cancers, inflammatory diseases, and other medical conditions.

Definition

ChEBI: 2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide is a benzodiazepine.

Biochem/physiol Actions

I-BET762 possesses anti-inflammatory property by controlling the pro-inflammatory gene expression. I-BET762 hinders the MYC (proto-oncogene) expression in cellular models. This action of I-BET762 might serve as an effective therapy in treating prostate cancer.

Synthesis

Example 1: (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetic acid (16.0 g, 40 mmol) was dissolved in THF, N,N-diisopropylethylamine (DIEA, 14 mL, 80 mmol) was added followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 30.4 g, 80 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Then THF solution of ethylamine (40 mL, 2 M, 80 mmol) was added. Stirring was continued for 48 h. The reaction mixture was concentrated under reduced pressure. The crude product was suspended in water and extracted with dichloromethane (DCM). The organic layer was dried with anhydrous sodium sulfate (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM/MeOH, 95:5) and the resulting solid was recrystallized in acetonitrile (MeCN). Subsequently, the solid was dissolved in DCM and precipitated with diisopropyl ether (1-Pr2O) to afford (S)-2-(6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (8 g, 47% yield) as a white solid. rf = 0.48 (DCM/MeOH, 90:10). Melting point >140°C (viscosity change).1H NMR (300 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.39 (d, J = 8.9 Hz, 1H), 7.37-7.31 (m, 2H), 7.20 (dd, J = 2.9, 8.9 Hz, 1H), 6.86 (d, J = 2.9 Hz, 1H). 6.40 (m, 1H), 4.62 (m, 1H), 3.80 (s, 3H), 3.51 (dd, J = 7.3, 14.1 Hz, 1H), 3.46-3.21 (m, 3H), 2.62 (s, 3H), 1.19 (t, J = 7.3 Hz, 3H). lc/ms: m/z 424 [M(35Cl)+H]+. Retention time 2.33 min.

target

BET

storage

Store at -20°C

References

[1] EDWIGE NICODEME. Suppression of inflammation by a synthetic histone mimic[J]. Nature, 2010, 468 7327: 1119-1123. DOI:10.1038/nature09589
[2] OLIVIER MIRGUET*. Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains[J]. Journal of Medicinal Chemistry, 2013, 56 19: 7501-7515. DOI:10.1021/jm401088k
[3] HOZEFA S BANDUKWALA. Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors.[J]. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109 36: 14532-14537. DOI:10.1073/pnas.1212264109
[4] JAKE E DELMORE. BET bromodomain inhibition as a therapeutic strategy to target c-Myc.[J]. Journal of Chemical Theory and Computation, 2011: 904-917. DOI:10.1016/j.cell.2011.08.017

GSK 525762A(1260907-17-2)Related Product Information

• (+)-JQ-1
• TRICHOSTATIN A
• GSK J1
• 2-N-HEXYL-4-PENTYNOIC ACID
• APICIDIN
• I-BET151 (GSK1210151A)
• RVX-208
• OTX015
• (2R,3R,4S,5R)-2-(6-aMino-9H-purin-9-yl)-5-((((1r,3S)-3-(2-(5-(tert-butyl)-1H-benzo[d]iMidazol-2-yl)ethyl)cyclobutyl)(isopropyl)aMino)Methyl)tetrahydrofuran-3,4-diol
• BI 2536
• PFI-1