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(Synonyms: NO-1886) 目录号 : GC44432

A lipoprotein lipase activator

NO-1886 Chemical Structure

Cas No.:133208-93-2

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5mg
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25mg
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产品文档

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产品描述

Lipoprotein lipase (LPL) mediates the hydrolysis of triglycerides in circulating very low density lipoproteins and chylomicrons. NO-1886 is an LPL activator that increases LPL mRNA and LPL activity in adipose tissue, myocardium, and skeletal muscle. This coincides with an elevation in post-heparin plasma LPL activity and LPL mass in rats. NO-1886 decreases plasma triglyceride concentration and increases plasma high-density lipoprotein cholesterol, resulting in inhibited development of atherosclerotic lesions in coronary arteries and aortas of rats and rabbits.

Chemical Properties

Cas No. 133208-93-2 SDF
别名 NO-1886
Canonical SMILES BrC1=CC(C#N)=C(NC(C2=CC=C(CP(OCC)(OCC)=O)C=C2)=O)C=C1
分子式 C19H20BrN2O4P 分子量 451.3
溶解度 DMF: 25 mg/ml,DMF:PBS(pH 7.2)(1:1): 0.5 mg/ml,DMSO: 25 mg/ml,Ethanol: 2 mg/ml 储存条件 Store at -20°C
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1 mM 2.2158 mL 11.0791 mL 22.1582 mL
5 mM 0.4432 mL 2.2158 mL 4.4316 mL
10 mM 0.2216 mL 1.1079 mL 2.2158 mL
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Research Update

Lipoprotein lipase activator NO-1886

Cardiovasc Drug Rev 2003 Summer;21(2):133-42.PMID:12847564DOI:10.1111/j.1527-3466.2003.tb00111.x.

Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoproteins such as very low-density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and a decrease in plasma high-density lipoprotein cholesterol (HDL-C). The increase in plasma TG and decrease in plasma HDL-C are risk factors for cardiovascular disease. Tsutsumi et al. hypothesized that elevating LPL activity would cause a reduction of plasma TG and an increase in plasma HDL-C, resulting in protection against the development of atherosclerosis. To test this hypothesis, Otsuka Pharmaceutical Factory, Inc. synthesized the LPL activator NO-1886. NO-1886 increased LPL mRNA and LPL activity in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and LPL mass in rats. NO-1886 also decreased plasma TG concentration and caused a concomitant rise in plasma HDL-C. Long-term administration of NO-1886 to rats and rabbits with experimental atherosclerosis inhibited the development of atherosclerotic lesions in coronary arteries and aortas. Multiple regression analysis suggested that the increase in plasma HDL-C and the decrease in plasma TG protect from atherosclerosis. The atherogenic lipid profile is changed to an antiatherogenic profile by increasing LPL activity, resulting in protection from atherosclerosis. Therefore, the LPL activator NO-1886 or other possible LPL activating agents are potentially beneficial for the treatment of hypertriglyceridemia, hypo-HDL cholesterolemia, and protection from atherosclerosis.

NO-1886 ameliorates glycogen metabolism in insulin-resistant HepG2 cells by GSK-3β signalling

J Pharm Pharmacol 2012 Feb;64(2):293-301.PMID:22221106DOI:10.1111/j.2042-7158.2011.01402.x.

Objectives: The aim of the study was to elucidate the possible role and mechanism of NO-1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. Methods: HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. Key findings: We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin-induced glucose consumption (from 2.89 ± 0.85 mm in the control to 0.57 ± 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO-1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin-resistant HepG2 cells. Maximum stimulation effects were observed with 10 µm NO-1886 for 24 h. Compared with the dimethyl sulfoxide-treated group, 2.5 µm NO-1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO-1886 increased the protein content of P-GSK-3βser(9) and decreased the protein level of GSK-3β in insulin-resistant HepG2 cells, but NO-1886 didn't change the protein levels of PI3-Kp85 and Akt2. Conclusion: Lipoprotein lipase activator NO-1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK-3 signalling.

NO-1886 suppresses diet-induced insulin resistance and cholesterol accumulation through STAT5-dependent upregulation of IGF1 and CYP7A1

J Endocrinol 2010 Jan;204(1):47-56.PMID:19815588DOI:10.1677/JOE-09-0278.

Insulin resistance and dyslipidemia are both considered to be risk factors for metabolic syndrome. Low levels of IGF1 are associated with insulin resistance. Elevation of low-density lipoprotein cholesterol (LDL-C) concomitant with depression of high-density lipoprotein cholesterol (HDL-C) increase the risk of obesity and type 2 diabetes mellitus (T2DM). Liver secretes IGF1 and catabolizes cholesterol regulated by the rate-limiting enzyme of bile acid synthesis from cholesterol 7alpha-hydroxylase (CYP7A1). NO-1886, a chemically synthesized lipoprotein lipase activator, suppresses diet-induced insulin resistance with the improvement of HDL-C. The goal of the present study is to evaluate whether NO-1886 upregulates IGF1 and CYP7A1 to benefit glucose and cholesterol metabolism. By using human hepatoma cell lines (HepG2 cells) as an in vitro model, we found that NO-1886 promoted IGF1 secretion and CYP7A1 expression through the activation of signal transducer and activator of transcription 5 (STAT5). Pretreatment of cells with AG 490, the inhibitor of STAT pathway, completely abolished NO-1886-induced IGF1 secretion and CYP7A1 expression. Studies performed in Chinese Bama minipigs pointed out an augmentation of plasma IGF1 elicited by a single dose administration of NO-1886. Long-term supplementation with NO-1886 recovered hyperinsulinemia and low plasma levels of IGF1 suppressed LDL-C and facilitated reverse cholesterol transport by decreasing hepatic cholesterol accumulation through increasing CYP7A1 expression in high-fat/high-sucrose/high-cholesterol diet minipigs. These findings indicate that NO-1886 upregulates IGF1 secretion and CYP7A1 expression to improve insulin resistance and hepatic cholesterol accumulation, which may represent an alternative therapeutic avenue of NO-1886 for T2DM and metabolic syndrome.

NO-1886, a lipoprotein lipase activator, attenuates vascular smooth muscle contraction in rat aorta

Eur J Pharmacol 2007 Jan 12;554(2-3):183-90.PMID:17109854DOI:10.1016/j.ejphar.2006.09.059.

The chemical compound [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester (NO-1886) is a lipoprotein lipase activator having beneficial effects on both diabetes control and the cardiovascular system. Preventing accumulation of lipids in the cell wall, in addition to improving insulin actions on vasculature, may indirectly contribute to the reducing effect of NO-1886 on vascular resistance. However, the direct effect of NO-1886 on vascular resistance, i.e., whether NO-1886 directly modulates the function of vascular endothelium and/or smooth muscle cells has not been investigated. In this study we therefore investigated the direct effect of NO-1886 on vascular contractility using rat aortic rings and cultured smooth muscle cell-line A10. The results show that administration of NO-1886 attenuated aortic contraction induced by phenylephrine and/or a high K(+) environment, in both the presence and absence of aortic endothelium. 1-(5-Chloronaphthalene-1-sulfonyl)homopiperazine hydrochloride (ML-9), a myosin light chain kinase (MLCK) inhibitor, blocked this inhibitory effect of NO-1886, whereas inhibitors of other signaling molecules such as calmodulin, protein kinase C and Rho-kinase had no effect. The vasorelaxant effect of NO-1886 was blocked in the absence of extracellular Ca(2+), or in the presence of the Ca(2+) channel inhibitor, verapamil. NO-1886 attenuated smooth muscle contraction induced by the cumulative addition of CaCl(2). In A10 cells, NO-1886 inhibited the membrane depolarization-induced initial peak of [Ca(2+)](i) in the presence of extracellular Ca(2+). This inhibition did not occur in the absence of extracellular Ca(2+). Taken together these results demonstrate that NO-1886 attenuates smooth muscle contraction and causes vasorelaxation by an extracellular Ca(2+)- and MLCK-dependent mechanism.

NO-1886 (ibrolipim), a lipoprotein lipase-promoting agent, accelerates the expression of UCP3 messenger RNA and ameliorates obesity in ovariectomized rats

Metabolism 2006 Feb;55(2):151-8.PMID:16423620DOI:10.1016/j.metabol.2005.08.007.

The synthetic compound NO-1886 (ibrolipim, [4-(4-bromo-2-cyano-phenylcarbamoyl)-benzyl]-phosphonic acid diethyl ester, CAS 133208-93-2) is a lipoprotein lipase (LPL)-promoting agent that decreases plasma triglycerides, increases high-density lipoprotein cholesterol levels, and prevents fat accumulation in high fat-fed rats. However, the effect of NO-1886 on body weight, fat accumulation, and energy expenditure in ovariectomized (OVX) rats is not clear. The primary aim of this study was to ascertain whether NO-1886 ameliorated obesity in OVX rats and to examine the effects on fatty acid oxidation-related enzymes. NO-1886 decreased accumulation of visceral fat and suppressed the increase in body weight resulting from the ovariectomy. NO-1886 decreased the respiratory quotient and increased expression of the fatty acid translocase messenger RNA (mRNA) in the liver, soleus muscle, and mesenteric fat. NO-1886 also increased the expression of fatty acid-binding protein mRNA in the liver and soleus muscle and the expression of the uncoupling protein 3 (UCP3) mRNA in the heart, soleus muscle, and mesenteric fat, but not in the brown adipose tissue. Furthermore, NO-1886 did not affect UCP1 and UCP2 in brown adipose tissue. Therefore, amelioration of obesity by NO-1886 in OVX rats is possibly because of an the increased expression of fatty acid oxidation-related enzymes and UCP3, both of which are related to fatty acid transfer and fat use. Our study indicates that the LPL-promoting agent NO-1886 may be potentially beneficial in the treatment of obesity and obesity-linked health problems in postmenopausal women.