1260907-17-2

Basic information

• Product Name: GSK 525762A
• Synonyms: GSK 525762A;(4S)-6-(4-Chlorophenyl)-N-ethyl-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetamide;I-BET-762;GSK 525762A (I-BET-762);GSK525762 (I-BET-762);GSK525762;4H-[1,2,4]Triazolo[4,3-a][1,4]benzodiazepine-4-acetamide, 6-(4-chlorophenyl)-N-ethyl-8-methoxy-1-methyl-, (4S)-;(4S)-6-(4-Chlorophenyl)-N-ethyl-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine-4-acetamide GSK 525762A I-BET-762
• CAS NO: 1260907-17-2
• Molecular Formula: C₂₂H₂₂ClN₅O₂
• Molecular Weight: 423.89538
• Product Categories: Apis;Inhibitors
• Mol File: 1260907-17-2.mol
• Article Data: 7

Chemical Properties

• Appearance: /
• 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)
• PKA: 15.71±0.46(Predicted)
• 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.
• CAS DataBase Reference: GSK 525762A(CAS DataBase Reference)
• NIST Chemistry Reference: GSK 525762A(1260907-17-2)
• EPA Substance Registry System: GSK 525762A(1260907-17-2)

Safety Data

• Hazardous Substances Data: 1260907-17-2(Hazardous Substances Data)

Usage

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 (Kd = 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.

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.

References

1) Nicodeme?et al.?(2010),?Suppression of inflammation by a synthetic histone mimic; Nature?468?1119 2) Mirguet?et al.?(2013),?Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains; J. Med. Chem.,?56?7501 3) Bandukwala?et al.?(2012),?Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors; Proc. Natl. Acad. Sci. USA,?109?14532 4) Delmore?et al.?(2011),?BET Bromodomain as a Therapeutic Strategy to Target c-Myc; Cell?146?904

Upstream product

• 75-04-7 ethylamine 
• 1300019-41-3 methyl [(3S)-2-[(1Z)-2-acetylhydrazino]-5-(4-chlorophenyl)-7-(methyloxy)-3H-1,4-benzodiazepin-3-yl]acetate 
• 67-56-1 methanol 
• 1300019-40-2 methyl 2-((4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-benzol[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)acetate 
• 1300019-41-3 methyl 2-[(3S,2Z)-2-(acetylhydrazono)-5-(4-chlorophenyl)-7-(methyloxy)-1,3-dihydro-1,4-benzodiazepin-3-yl]acetate 
• 1300019-43-5 (S)-methyl 2-(5-(4-chlorophenyl)-7-methoxy-2-thioxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)acetate 
• 1300019-46-8 (S)-methyl 2-(5-(4-chlorophenyl)-7-methoxy-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)acetate 
• 1300019-48-0 methyl N¹-[2-[(4-chlorophenyl)carbonyl]-4-(methyloxy)phenyl]-N²-{[(9H-fluoren-9-ylmethyl)oxy]carbonyl}-L-α-asparaginate 
• 91713-54-1 [2-amino-5-(methyloxy)phenyl](4-chlorophenyl)methanone 
• 38527-50-3 2-methyl-6-(methoxy)-3,1-benzoxazin-4-one 
• 6705-03-9 2-Amino-5-methoxybenzoic acid 
• 1300019-38-8 [(4S)-6-(4-chlorophenyl)-1-methyl-8-(methyloxy)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]acetic acid 
• 873-77-8 (4-chlorphenyl)magnesium bromide 

Downstream Products

• 1352936-97-0 2-{(4S)-6-(4-chlorophenyl)-1-methyl-8-[4-(methyloxy)phenyl]-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl}-N-ethylacetamide 
• 1352937-00-8 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-5-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide 
• 1352937-04-2 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(1H-pyrazol-4-yl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide 
• 1352937-10-0 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(2-methylphenyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide 
• 1352937-16-6 2-[(4S)-6-(4-chlorophenyl)-1-methyl-8-(3-pyridinyl)-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide 
• 1352937-21-3 (S)-2-(6-(4-chlorophenyl)-8-(3-methoxyphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-26-8 (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(pyridin-4-yl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-30-4 (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-36-0 (S)-2-(6-(4-chlorophenyl)-8-(3-((ethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-41-7 (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(3-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-45-1 (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-(pyrrolidin-1-ylmethyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-49-5 (S)-2-(6-(4-chlorophenyl)-1-methyl-8-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-54-2 (S)-2-(6-(4-chlorophenyl)-8-(4-((ethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 
• 1352937-59-7 (S)-2-(6-(4-chlorophenyl)-8-(4-((dimethylamino)methyl)phenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide 

Relevant articles and documents

Preparation of Methyltriazolo[1,4]benzodiazepine via Oxidative Activation of a Thiolactam for the Synthesis of BET Inhibitor Molibresib

A novel oxidative activation of a thiolactam was developed for the preparation of methyltriazolo[1,4]benzodiazepine in a single step. A sulfenic acid (R-SOH) was proposed as the activated intermediate with the concurrent formation of acetylhydrazone from acethydrazide and cyclocondensation to the triazole. A version of the method with 35% peracetic acid was scaled up to 40 kg as a part of the new route for the synthesis of BET inhibitor molibresib (GSK525762). The thiolactam was prepared from commercially available (2-amino-5-methoxyphenyl)(4-chlorophenyl)methanone in two steps in 66% yield. The concise four-step synthesis delivered 52 kg of molibresib of >99.9% ee in an overall 41% yield from the ketone. The condition for the methyltriazole was mild and free of racemization of the sensitive stereocenter. The oxidative method, with several advantages to the known methods, should be applicable to the synthesis of alkyltriazoles from other thiolactams and acylhydrazines.

Discovery of epigenetic regulator i-bet762: Lead optimization to afford a clinical candidate inhibitor of the bet bromodomains

The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structure-activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers.

Bromodomain Inhibitors For Treating Autoimmune And Inflammatory Diseases

The use of compounds in the treatment of autoimmune and inflammatory diseases or conditions, pharmaceutical compositions containing such compounds and to methods for identifying compounds for use in the treatment of such diseases or conditions.