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非诺贝特

非诺贝特用途

Fenofibrate是 PPARα 激动剂,EC50 为30 μM。

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非诺贝特名称

[ CAS 号 ]:
49562-28-9

[ 中文名 ]:
非诺贝特

[ 英文名 ]:
Fenofibrate

[中文别名 ]:

[英文别名 ]:

Lipantil
Procetofen
Fenofibrate
Lipidil
Tricor
Lipanthyl
Supralip
Secalip

非诺贝特生物活性

[ 描述 ]:

Fenofibrate是 PPARα 激动剂,EC50 为30 μM。

[ 相关类别 ]:

信号通路 >> 自噬 >> 自噬

信号通路 >> 代谢酶/蛋白酶 >> 细胞色素P450

信号通路 >> 细胞周期/DNA损伤 >> PPAR

研究领域 >> 心血管疾病

[ 靶点 ]

CYP2C19:0.2 μM (IC50)

CYP2B6:0.7 μM (IC50)

CYP2C9:9.7 μM (IC50)

CYP2C8:4.8 μM (IC50)

CYP3A4:142.1 μM (IC50)

PPARα:30 μM (IC50)

[体外研究]

非诺贝特是一种相对有效的CYP2B6抑制剂(IC50 = 0.7±0.2μM)和CYP2C19(IC50 = 0.2±0.1μM)。非诺贝特也是CYP2C8的中度抑制剂(IC50 = 4.8±1.7μM)和CYP2C9(IC50 =9.7μM)[1]。非诺贝特以高于PPARα的亲和力结合并抑制细胞色素P450环加氧酶(CYP)2C。非诺贝特是一种众所周知的PPARα激动剂,但对209种常用处方药和相关异生素的体外评估表明,非诺贝特也是细胞色素P450环氧化酶(CYP)2C的有效抑制剂。非诺贝特对CYP2C的亲和力比对PPARα(EC50 =30μM)高> 10倍(EC50 = 2.39±0.4μM)。低剂量的非诺贝特抑制CYP2C8活性而不激活PPARα[2]。

[体内研究]

在这种低剂量(10μg/ g /天)下每日摄入非诺贝特可抑制由CYP2C8过度表达诱导的视网膜和脉络膜新生血管形成,分别为29％(P = 0.021)和36％(P = 1.2×10-9)[2]。

[激酶实验]

非诺贝特，他汀类药物（阿托伐他汀，洛伐他汀，普伐他汀，辛伐他汀和辛伐他汀酸，辛伐他汀的活性形式）和格列吡嗪对重组人CYP1A2，CYP2B6，CYP2C8，CYP2C9，CYP2C19，CYP2D6和CYP3A4的半数抑制浓度（IC50s）使用荧光CYP450抑制测定法测定。简而言之，将药物溶解在甲醇或乙腈中。在96孔测定板中，将药物在含有辅因子的溶液中稀释至一系列浓度，所述辅因子包括NADP +（终浓度1.3mM），MgCl 2（终浓度3.3m M），葡萄糖-6-磷酸（G6P，终浓度3.3mM）。）和葡萄糖-6-磷酸脱氢酶（终浓度0.4U / mL）。将混合物在37℃下预温育10分钟。将酶和荧光底物在磷酸钠反应缓冲液（pH 7.4，终浓度200mM）中稀释至所需浓度并混合。通过将酶和底物混合物添加到辅因子和药物混合物中来开始反应。所有测定的最终反应体积为200μL。在37℃下孵育预定的时间段（15至45分钟）后，通过添加75μL猝灭溶液（0.5M Tris碱或2N NaOH）终止反应。使用BioTek Synergy 2荧光读数器测定荧光。每种药物以八种浓度一式两份进行测试。为了估计IC 50，使用针对背景校正的净荧光计算抑制百分比。然后将抑制百分比的值拟合到三或四参数对数逻辑模型[1]。

[动物实验]

小鼠[2]使用小鼠氧诱导的视网膜病变（OIR）模型。简言之，为了诱导视网膜新生血管形成，小鼠幼仔及其哺乳母亲暴露于从P7到P12的75±3％氧气。用于较高剂量的非诺贝特（F6020）治疗（100mg / kg /天）。将非诺贝特溶解在玉米油中以制备100mg / mL溶液，并将纯玉米油用作媒介物对照。对于较低剂量的治疗（10mg / kg /天），将非诺贝特溶解在10％DMSO，D2650中以制备10mg / mL溶液，并使用10％DMSO作为媒介物对照。回到室内空气后，每天从P12到P16口服强抗诺非贝特（100或10mg / kg）或载体对照。在P17，在安乐死后立即摘出眼，并在室温下在PBS中的4％多聚甲醛中固定1小时。然后解剖视网膜并在室温下用Alexa Fluor 594缀合的同工凝集素GS-IB4（10μg/ mL）染色过夜。用PBS洗涤后，将视网膜安装到显微镜载玻片上，感光体侧朝下并嵌入SlowFade抗褪色封固剂中。使用具有图像软件的荧光显微镜拍摄视网膜图像。分析视网膜新血管形成。

[参考文献]

[1]. Schelleman H, et al. Pharmacoepidemiologic and in vitro evaluation of potential drug-drug interactions of sulfonylureas with fibrates and statins. Br J Clin Pharmacol. 2014 Sep;78(3):639-48.

[2]. Gong Y, et al. Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis. EBioMedicine. 2016 Sep 30. pii: S2352-3964(16)30448-0.

[相关活性小分子]

非诺贝特物理化学性质

[ 密度 ]:
1.2±0.1 g/cm3

[ 沸点 ]:
469.8±35.0 °C at 760 mmHg

[ 熔点 ]:
80-81ºC

[ 分子式 ]:
C₂₀H₂₁ClO₄

[ 分子量 ]:
360.831

[ 闪点 ]:
165.4±24.9 °C

[ 精确质量 ]:
360.112823

[ PSA ]:
52.60000

[ LogP ]:
4.80

[ 外观性状 ]:
白色或淡黄色结晶粉末

[ 蒸汽压 ]:
0.0±1.2 mmHg at 25°C

[ 折射率 ]:
1.547

[ 储存条件 ]:
Store at RT

[ 水溶解性 ]:
Practically insoluble in water, very soluble in methylene chloride, slightly soluble in ethanol (96 per cent)

非诺贝特MSDS

详细MSDS(安全技术说明书)

非诺贝特毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: UA2453400

CHEMICAL NAME :: Propanoic acid, 2-(4-(4-chlorobenzoyl)phenoxy)-2-methyl-, 1-methylethyl ester

CAS REGISTRY NUMBER :: 49562-28-9

LAST UPDATED :: 199612

DATA ITEMS CITED :: 14

MOLECULAR FORMULA :: C20-H21-Cl-O4

MOLECULAR WEIGHT :: 360.86

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >2 gm/kg

TOXIC EFFECTS :: Liver - other changes

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S873,1995

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 1600 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: ARZNAD Arzneimittel-Forschung. Drug Research. (Editio Cantor Verlag, Postfach 1255, W-7960 Aulendorf, Fed. Rep. Ger.) V.1- 1951- Volume(issue)/page/year: 26,885,1976

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >4 gm/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S873,1995

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - hamster

DOSE/DURATION :: >5 gm/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: AJMEAZ American Journal of Medicine. (Technical Pub., 875 Third Ave., New York, NY 10022) V.1- 1946- Volume(issue)/page/year: 83(Suppl 5B),26,1987 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2730 mg/kg/13W-I

TOXIC EFFECTS :: Liver - changes in liver weight Blood - normocytic anemia Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S881,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 9100 mg/kg/52W-I

TOXIC EFFECTS :: Liver - other changes Nutritional and Gross Metabolic - weight loss or decreased weight gain Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S903,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 81900 mg/kg/13W-I

TOXIC EFFECTS :: Blood - normocytic anemia Blood - changes in platelet count Related to Chronic Data - death

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S923,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 36400 mg/kg/52W-I

TOXIC EFFECTS :: Gastrointestinal - hypermotility, diarrhea Blood - normocytic anemia

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S949,1995 ** REPRODUCTIVE DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 84 gm/kg

SEX/DURATION :: male 9 week(s) pre-mating female 2 week(s) pre-mating - 7 day(s) after conception

TOXIC EFFECTS :: Reproductive - Paternal Effects - other effects on male Reproductive - Maternal Effects - other effects

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S973,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 22 gm/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants) Reproductive - Specific Developmental Abnormalities - musculoskeletal system Reproductive - Effects on Newborn - behavioral

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S983,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 1100 mg/kg

SEX/DURATION :: female 7-17 day(s) after conception

TOXIC EFFECTS :: Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S983,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 26 gm/kg

SEX/DURATION :: female 17-21 day(s) after conception lactating female 21 day(s) post-birth

TOXIC EFFECTS :: Reproductive - Fertility - other measures of fertility Reproductive - Effects on Newborn - stillbirth Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 23(Suppl 4),S1001,1995

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 5855 mg/kg

SEX/DURATION :: female 7-16 day(s) after conception

TOXIC EFFECTS :: Reproductive - Fertility - post-implantation mortality (e.g. dead and/or resorbed implants per total number of implants)

REFERENCE :: PHTOEH Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- Volume(issue)/page/year: 64,286,1989

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

DOSE :: 117 mg/kg

SEX/DURATION :: female 7-16 day(s) after conception

TOXIC EFFECTS :: Reproductive - Specific Developmental Abnormalities - urogenital system Reproductive - Specific Developmental Abnormalities - other developmental abnormalities

REFERENCE :: PHTOEH Pharmacology and Toxicology (Copenhagen). (Munksgaard International Pub., POB 2148, DK-1016 Copenhagen K, Denmark) V.60- 1987- Volume(issue)/page/year: 64,286,1989

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非诺贝特安全信息

[ 个人防护装备 ]:
dust mask type N95 (US);Eyeshields;Gloves

[ 危害码 (欧洲) ]:
Xn:Harmful

[ 风险声明 (欧洲) ]:
R22

[ 安全声明 (欧洲) ]:
S36

[ 危险品运输编码 ]:
NONH for all modes of transport

[ WGK德国 ]:
3

[ RTECS号 ]:
UA2453400

[ 海关编码 ]:
2932999099

非诺贝特合成路线

详细合成路线

非诺贝特上下游产品

非诺贝特上游产品

非诺贝特下游产品

非诺贝特海关

[ 海关编码 ]: 2932999099

[ 中文概述 ]:
2932999099. 其他仅含氧杂原子的杂环化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0%

[ 申报要素 ]: 品名, 成分含量, 用途

[ Summary ]:
2932999099. other heterocyclic compounds with oxygen hetero-atom(s) only. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

非诺贝特文献

Pharmacological protection of retinal pigmented epithelial cells by sulindac involves PPAR-α.

Proc. Natl. Acad. Sci. U. S. A. 111(47) , 16754-9, (2014)

The retinal pigmented epithelial (RPE) layer is one of the major ocular tissues affected by oxidative stress and is known to play an important role in the etiology of age-related macular degeneration ...

Modulators of hepatic lipoprotein metabolism identified in a search for small-molecule inducers of tribbles pseudokinase 1 expression.

PLoS ONE 10 , e0120295, (2015)

Recent genome wide association studies have linked tribbles pseudokinase 1 (TRIB1) to the risk of coronary artery disease (CAD). Based on the observations that increased expression of TRIB1 reduces se...

Hypolipidemic and Hepatic Steatosis Preventing Activities of the Wood Ear Medicinal Mushroom Auricularia auricula-judae (Higher Basidiomycetes) Ethanol Extract In Vivo and In Vitro.

Int. J. Med. Mushrooms 17 , 723-34, (2015)

Obesity, a rapidly growing threat to human health worldwide, is responsible for a large proportion of the total burden of disease. Therefore, obesity control could be a vital scheme to prevent many di...

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