|2-(2-氯苯基)-4-[3-(二甲基氨基)苯基]-5-甲基-1H-吡唑并[4,3-c]吡啶-3,6(2H,5H)-二酮|CsnPharm

CAS No.: 1218942-37-0

2-(2-Chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione Catalog No. CSN13646

Synonyms: GKT137831;GKT831;GTK-831

GKT137831 is a specific dual Nox1/Nox4 inhibitor with Ki of 140±40 nM and 110±30 nM and a potent inhibitor of fibrosis and hepatocyte apoptosis.

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纯度 & 质量文件批次:

靶点选择性

生物活性

实验方案

技术信息

生物活性

靶点 NADPH Oxidase 1

Ki:140±40nM NADPH Oxidase 4

Ki:110±30nM
描述Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX), including NOX1/NOX4 components, generates reactive oxygen species (ROS) in hepatic stellate cells (HSCs) during liver fibrosis. GKT137831 is a potent drug-like small molecule that inhibits NOX1/NOX4 with Ki value of 110nM and 140nM, respectively. When tested at 10μM, GKT137831 did not show any signiﬁcant inhibition of 170 proteins like G-protein coupled receptors, kinases, ion channels and so on. Incubating with GKT137831 also reduced expression levels of collagen α1(I) and Acta2 mRNA to the same low levels in both activated SOD1mu and WT HSCs. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O2) for 72 hours with or without GKT137831. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O2) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure, the results showed that targeting Nox4 with GKT137831 inhibited hypoxia-induced increases in TGF-β1 and reductions in PPARγ expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. In apolipoprotein E-deficient mice with deletion of Nox1 but not Nox4, GKT137831 (60 mg/kg/d) attenuated diabete mellitus accelerated atherosclerosis, correlating with reduced reactive oxygen species formation, attenuation of chemokine expression, vascular adhesion of leukocytes, macrophage infiltration, and reduced expression of pro-inflammatory and profibrotic markers. Moreover, in Ang II-infused c-hNox4Tg mice, GKT137831 was mixed in standard chow diet and treatment with a dose of 40 mg/kg/day. The c-hNox4Tg mice exhibited approximately 10-fold increase in Nox4 protein expression and 8-fold increase in the production of reactive oxygen species, and manifested cardiac interstitial fibrosis, suggesting that GKT137831 abolished the increase in oxidative stress, suppressed Akt-mTOR and NF-κB signaling pathway and attenuated cardiac remodeling.

动物研究

剂量

Rat: 1 mg/kg^[3] (i.p.) Mice: 10 mg/kg - 40 mg/kg^[4] (p.o.), 60 mg/kg^[2] (i.g.), 60 mg/kg^[5] (p.o.)

给药途径

i.p., p.o., i.g.

动物药代数据

Animal	Mice^[4]
Dose	5 mg/kg
Administration	p.o.
C_max	2495 ng/ml
T_last	1.5 h
C_last	241 ng/ml
AUC_0→t	1578 ng·h/ml

临床研究

NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
NCT03740217	Phase 1	Phase 1	Not yet recruiting	April 15, 2019	-
NCT03226067	Primary Biliary Cirrhosis	Phase 2	Active, not recruiting	September 26, 2019	-
NCT02010242	Type 2 Diabetes Mellitus With ... more >>Diabetic Nephropathy Collapse <<	Phase 2	Completed	-	-

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 2.5326 mL
- 12.6629 mL
- 25.3258 mL
- 5 mM
- 0.5065 mL
- 2.5326 mL
- 5.0652 mL
- 10 mM
- 0.2533 mL
- 1.2663 mL
- 2.5326 mL

技术信息

CAS号

1218942-37-0

储存条件

粉末: Sealed in dry,Store in freezer, under -20°C

液体: -20°C:3-6 月 -80°C:12月

分子式

C21H19ClN4O2

运输

蓝冰

分子量

394.85

别名

GKT137831;GKT831;GTK-831

溶解度

DMSO	76.0 mg/mL (192.5 mM) warming
Water	Insoluble
Ethanol	Insoluble

动物实验配方

2% DMSO+2% Tween 80+30% PEG 300+water

9 mg/mL

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靶点	Description	IC50
NADPH Oxidase 1		Ki:140±40nM
NADPH Oxidase 4		Ki:110±30nM

2-(2-Chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione Catalog No. CSN13646

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