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盐酸克立咪唑

盐酸克立咪唑用途

Clemizole hydrochloride 是一种 H1 组胺受体 (H1 histamine receptor) 拮抗剂,抑制 HCV 复制。

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盐酸克立咪唑名称

[ CAS 号 ]:
1163-36-6

[ 中文名 ]:
盐酸氯咪唑

[ 英文名 ]:
Clemizole hydrochloride

[中文别名 ]:

[英文别名 ]:

EINECS 214-605-4
clemizole HCl
Clemizole hydrochloride
MFCD00051435
Clemizole (hydrochloride)

盐酸克立咪唑生物活性

[ 描述 ]:

Clemizole hydrochloride 是一种 H1 组胺受体 (H1 histamine receptor) 拮抗剂,抑制 HCV 复制。

[ 相关类别 ]:

信号通路 >> 代谢酶/蛋白酶 >> HCV蛋白酶

信号通路 >> 抗感染 >> HCV

信号通路 >> G 蛋白偶联受体/G 蛋白 >> 组胺受体

信号通路 >> 免疫及炎症 >> 组胺受体

研究领域 >> 炎症/免疫

[ 靶点 ]

IC50: 24 nM (NS4B)[1] H1 histamine receptor[1]

[体外研究]

发现克立咪唑盐酸盐抑制细胞培养物中的HCV RNA复制,其通过抑制NS4B的RNA结合介导,对宿主细胞几乎没有毒性。克立咪唑对W55R突变体J6/JFH RNA的EC50为~18μM(野生型RNA的EC50的2.25倍)[1]。克立咪唑是TRPC5通道的新型抑制剂。克立咪唑有效阻断TRPC5电流和Ca2 +进入低微摩尔范围(IC50 =1.0-1.3μM)。克立咪唑对TRPC5的选择性比TRPC4β高6倍(IC50 =6.4μM),是TRPC5最接近的结构相对,对TRPC3(IC50 =9.1μM)和TRPC6(IC50 =11.3μM)的选择性几乎是10倍。克立咪唑盐酸盐作为TRPC5的新型阻断剂,半数最大抑制浓度为1.1μM。浓度-反应曲线证实了克立咪唑对TRPC5的浓度依赖性阻断,并且显示出明显的IC50为1.1±0.04μM[2]。

[体内研究]

克立咪唑盐酸盐具有出乎意料的短血浆半衰期(在0.15小时测量);它很快被生物转化为葡萄糖醛酸苷(M14)和脱烷基化代谢物(M12),进入C57BL/6J小鼠的各种代谢产物中[3]。

[细胞实验]

将Huh7.5细胞维持在补充有1％L-谷氨酰胺，1％青霉素，1％链霉素，1x非必需氨基酸和10％FBS的DMEM中。用0.05％胰蛋白酶-0.02％EDTA处理后，每周两次传代细胞系，并以1：5的稀释度接种。将亚汇合的Huh7.5细胞用胰蛋白酶消化并通过在700g离心5分钟收集。然后将细胞在冰冷的无RNase的PBS中洗涤三次，并以1.5×10 7个细胞/ mL重悬于PBS中。用于电穿孔的野生型或突变体FL-J6 / JFH-5'C19Rluc2AUbi RNA通过使用T7 MEGAscript试剂盒转录XbaI线性化DNA模板，然后纯化（RNA转录和荧光标记）而产生。我们将5μgRNA与400μL经洗涤的Huh7.5细胞在2mm间隙比色杯（BTX）中混合，并立即用BTX-830电穿孔仪脉冲（0.82kV，5次99μs脉冲）。在25℃下恢复10分钟后，将脉冲细胞稀释到10mL预热的生长培养基中。将来自几次电穿孔的细胞合并到普通原种中并接种在6孔板中（每孔5×10 5个细胞）。 24小时后，更换培养基，并在筛选中鉴定的各种抑制性化合物（例如盐酸克立咪唑）的连续稀释液存在下培养细胞。分析了所鉴定的18种市售化合物中的17种。未处理的细胞用作水溶性化合物的阴性对照。对于溶解在DMSO中的化合物（例如盐酸克立咪唑），未处理的细胞在相应浓度的溶剂存在下生长，作为阴性对照。每天更换中等。处理72小时后，对细胞进行基于Alamar Blue的活力测定和荧光素酶测定。处理72小时后，将细胞在10％Alamar Blue试剂存在下于37℃温育3小时。然后扫描平板并使用FLEXstation II 384检测荧光。根据抑制性化合物的溶剂（例如盐酸克立咪唑），水或DMSO，信号相对于未经处理的样品或在DMSO存在下生长的样品进行标准化[1] ]。

[动物实验]

小鼠[3]通过口腔克立咪唑给予8只对照NOG小鼠和8只人源化TK-NOG小鼠25mg / kg，并在给药后30分钟收集血液样品。通过口腔克立咪唑给予C57BL / 6J小鼠（每个时间点3只）25mg / kg，并且在给药后15和30分钟以及1,2,4和6小时收集血液样品用于分析。对于DDI研究，给予8只人源化TK-NOG小鼠克立咪唑（口服25mg / kg），有或没有利托那韦（20mg / kg口服），并在给药后30分钟收集血样。在存在或不存在利托那韦（口服20mg / kg）的情况下，还用Debrisoquine（10mg / kg口服）处理这些小鼠中的6只，并在2小时后获得血浆样品用于分析。

[参考文献]

[1]. Einav S, et al. Discovery of a hepatitis C target and its pharmacological inhibitors by microfluidic affinity analysis. Nat Biotechnol. 2008 Sep;26(9):1019-27.

[2]. Richter JM, et al. Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5. Mol Pharmacol. 2014 Nov;86(5):514-21.

[3]. Nishimura T, et al. Using chimeric mice with humanized livers to predict human drug metabolism and a drug-drug interaction. J Pharmacol Exp Ther. 2013 Feb;344(2):388-96.

[相关活性小分子]

盐酸克立咪唑物理化学性质

[ 密度 ]:
1.25 g/cm3

[ 沸点 ]:
506.1ºC at 760 mmHg

[ 熔点 ]:
241 °C

[ 分子式 ]:
C₁₉H₂₁Cl₂N₃

[ 分子量 ]:
362.296

[ 闪点 ]:
259.9ºC

[ 精确质量 ]:
361.111267

[ PSA ]:
21.06000

[ LogP ]:
5.07370

[ 外观性状 ]:
固体;White to Almost white powder to crystal

[ 蒸汽压 ]:
2.29E-10mmHg at 25°C

[ 储存条件 ]:
0-10°C;存放于惰性气体之中;避免空气,加热

[ 水溶解性 ]:
水溶性：可溶；不溶：二乙醚

盐酸克立咪唑毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: DD6730000

CHEMICAL NAME :: Benzimidazole, 1-(p-chlorobenzyl)-2-(1-pyrrolidinylmethyl)-, monohydrochloride

CAS REGISTRY NUMBER :: 1163-36-6

LAST UPDATED :: 199512

DATA ITEMS CITED :: 7

MOLECULAR FORMULA :: C19-H20-Cl-N3.Cl-H

MOLECULAR WEIGHT :: 362.33

WISWESSER LINE NOTATION :: T56 BN DNJ B1R DG& C1- AT5NTJ &GH

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 :: 1950 mg/kg

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

REFERENCE :: JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 49,18,1960

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 74 mg/kg

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

REFERENCE :: JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 49,18,1960

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

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 837 mg/kg

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

REFERENCE :: JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 49,18,1960

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 290 mg/kg

TOXIC EFFECTS :: Autonomic Nervous System - smooth muscle relaxant (mechanism undefined, spasmolytic)

REFERENCE :: FRPSAX Farmaco, Edizione Scientifica. (Casella Postale 227, 27100 Pavia, Italy) V.8-43 1953-88 For publisher information, see FRMCE8 Volume(issue)/page/year: 14,194,1959

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 75 mg/kg

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

REFERENCE :: JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 49,18,1960

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - guinea pig

DOSE/DURATION :: 26 mg/kg

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

REFERENCE :: AIPTAK Archives Internationales de Pharmacodynamie et de Therapie. (Heymans Institute of Pharmacology, De Pintelaan 185, B-9000 Ghent, Belgium) V.4- 1898- Volume(issue)/page/year: 113,313,1958 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 182 gm/kg/26W-C

TOXIC EFFECTS :: Nutritional and Gross Metabolic - weight loss or decreased weight gain

REFERENCE :: JAPMA8 Journal of the American Pharmaceutical Association, Scientific Edition. (Washington, DC) V.29-49, 1940-60. For publisher information, see JPMSAE. Volume(issue)/page/year: 49,18,1960

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盐酸克立咪唑安全信息

[ 符号 ]:

GHS07

[ 信号词 ]:
Warning

[ 危害声明 ]:
H302

[ 警示性声明 ]:
P301 + P312 + P330

[ 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 ]:
DD6730000

盐酸克立咪唑文献

Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5.

Mol. Pharmacol. 86(5) , 514-21, (2014)

Canonical transient receptor potential channel 5 (TRPC5) is a nonselective, Ca(2+)-permeable cation channel that belongs to the large family of transient receptor potential channels. It is predominant...

Drug screening in Scn1a zebrafish mutant identifies clemizole as a potential Dravet syndrome treatment.

Nat. Commun. 4 , 2410, (2013)

Dravet syndrome is a catastrophic pediatric epilepsy with severe intellectual disability, impaired social development and persistent drug-resistant seizures. One of its primary monogenic causes are mu...

Clemizole hydrochloride. Parvez M

Acta Crystallogr. C Struct. Chem. 52(4) , 904-905, (1996)

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