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GW3965 hydrochloride

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Chemical Structure| 405911-17-3 同义名 : GW 3965 (hydrochloride);GW3965 HCl
CAS号 : 405911-17-3
货号 : A150197
分子式 : C33H32Cl2F3NO3
纯度 : 98%
分子量 : 618.513
MDL号 : -
存储条件：

粉末 Keep in dark place,Inert atmosphere,Room temperature

液体 -20°C:3-6个月-80°C:12个月
溶解度 :

DMSO: 105 mg/mL(169.76 mM)，配合低频超声助溶，注意：DMSO长时间开封后，会吸水并导致溶解能力下降，请避免使用长期开封的DMSO
动物实验配方：

IP 2% DMSO+2% Tween80+30% PEG300+water 1 mg/mL clear

PO 0.5% CMC-Na 50 mg/mL suspension

生物活性
描述 LXRs (Liver X receptors) are ligand-activated transcription factors of the nuclear receptor superfamily, consist of two LXR isoforms termed alpha and beta. It is characterized as key transcriptional regulators of lipid and carbohydrate metabolism. GW3965 is a potent and selective tertiary-amine-derived nonsteroidal LXR agonist with EC50 values of 190 and 30 nM for LXRα and LXRβ (measured by LXRα cell-based reporter gene assay), respectively. It could recruit the steroid receptor coactivator 1 to human LXRα in a cell-free ligand-sensing assay with an EC50 of 125 nM. A single dose of GW3965 at dose of 10mg/kg achieved oral bioavailability of 70% at 2h post treatment in mice. The pharmacological activity could be evaluated in mce by dosing at 10 mg/kg bid for 14 days, as the expression of reverse cholesterol transporter ABCA1, a target gene of LXR, was increased 8-fold in the small intestine and 7-fold in peripheral macrophages by day 3, while plasma levels of HDLc increased 30% at day 3 and was maintained until day 14[1]. Through activation of GW3965, GW3965 affected pathways of glucose and lipid metabolism. It altered fat tissue distribution in ob/ob female mice[2]. GW3965 exhibited potent antiatherogenic activity in both two models, LDLR-/- mice and apoE-/- mice, as reducing lesion area by 34%-53%[3]. As LXRs and their ligands are negative regulators of macrophage inflammatory gene expression, treatment with GW3965 could reduce inflammation in a model of irritant contact dermatitis[4] and alter adipose tissue inflammation in ob/ob female mice[2].
细胞研究
细胞系 浓度 检测类型 检测时间 活动说明 数据源
CHO cells Function assay Agonist activity at human LXR beta receptor expressed in CHO cells by reporter assay, EC50=0.41 μM 17034119
CHOK1 cells Function assay 24 h Agonist activity at Gal4-tagged LXRbeta (unknown origin) expressed in CHOK1 cells after 24 hrs by luciferase reporter gene assay, EC50=0.42 μM 25677664
COS7 cells Function assay Activation of LXRbeta co-transfected in COS7 cells with RXRalpha by reporter transactivation assay, EC50=0.015 μM 17416521
实验方案
1mg 5mg 10mg

1 mM

5 mM

10 mM

1.62mL

0.32mL

0.16mL

8.08mL

1.62mL

0.81mL

16.17mL

3.23mL

1.62mL
参考文献

[1]Collins JL, Fivush AM, et al. Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem. 2002 May 9;45(10):1963-6.

[2]Archer A, Stolarczyk E, et al. LXR activation by GW3965 alters fat tissue distribution and adipose tissue inflammation in ob/ob female mice. J Lipid Res. 2013 May;54(5):1300-11.

[3]Joseph SB, McKilligin E, et al. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7604-9.

[4]Joseph SB, Castrillo A, et al. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003 Feb;9(2):213-9. Epub 2003 Jan 13.

[5]Guo D, Reinitz F, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway. Cancer Discov. 2011 Oct;1(5):442-56.

[6]He Q, Pu J, et al. Liver X receptor agonist treatment attenuates cardiac dysfunction in type 2 diabetic db/db mice. Cardiovasc Diabetol. 2014 Nov 22;13:149.

[7]Spyridon M, Moraes LA, et al. LXR as a novel antithrombotic target. Blood. 2011 May 26;117(21):5751-61.