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阿洛司他丁酸

阿洛司他丁酸用途

E 64c 是半胱氨酸蛋白酶 (cysteine proteases) 天然环氧化物抑制剂的衍生物,也是钙离子激活中性蛋白酶 (CANP) 的抑制剂和组织蛋白酶C (cathepsin C) 的弱不可逆抑制剂。

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阿洛司他丁酸名称

[ CAS 号 ]:
76684-89-4

[ 中文名 ]:
阿洛司他丁酸

[ 英文名 ]:
E-64c

[英文别名 ]:

Loxistatin acid
L-TRANS-EPOXYSUCCINYL-LEU-3-METHYLBUTYLAMIDE
E-64c,EP 475
Inhibitorforthiolprotease
anecarboxylicacid

阿洛司他丁酸生物活性

[ 描述 ]:

[ 相关类别 ]:

信号通路 >> 代谢酶/蛋白酶 >> 组织蛋白酶

研究领域 >> 代谢疾病

[ 靶点 ]

Cysteine proteases[1], CANP[2], Cathepsin C[3].

[体外研究]

E-64c,天然存在的半胱氨酸蛋白酶环氧化物抑制剂的衍生物,含有木瓜蛋白酶;特别是关于配体与催化结合位点中保守残基的氢键和疏水相互作用[1]。 E 64c(k2/Ki = 140±5M-1s-1)被证明是不可逆组织蛋白酶C抑制剂发展的先导结构[3]。

[体内研究]

血浆E-64c的t-1/2为0.48小时。在该剂量下不存在E-64c的血液动力学效应。使用双向方差分析,再灌注(p = 0.0016)或E-64c(p = 0.0226)本身对梗塞面积的影响是显着的。在将A组与B组和C组与D组进行比较时,E-64c处理组(A组和C组)中CPK的消耗略低于注射媒介物的组(B组和D组)。单独使用E-64c的效果不足可以通过早期给药和相对短的t-1/2来解释。由于NCO-700的有效性已经确定,6),7)我们的研究结果可能表明E-64c对梗塞面积和CPK含量的影响很小但有益[2]。

[动物实验]

狗[2]研究在83只杂种狗中进行，平均体重为11.2kg。用静脉注射硫脲钠（7mg / kg）麻醉它们。在闭塞前和A组再灌注后立即给予溶解在饱和碳酸氢钠中的E-64c（100mg / kg）静脉推注（n = 17），而B组（n = 17）仅接受载体溶液。在这些时候。在剩余的49只狗（C组和D组）中，LAD在相同水平永久性结扎并静脉推注Loxistatin酸（100mg / kg）（C组; n = 24）或仅用载体（D组; n组）在结扎前和结扎后1小时给予= 25）。 E-64c的剂量设计用于其在临床实践中的可能用途，估计的心肌内洛西他汀酸分子浓度是mCANP总量的1,000倍[2]。

[参考文献]

[1]. Khan MS, et al. Design, synthesis, evaluation and thermodynamics of 1-substituted pyridylimidazo[1,5-a]pyridine derivatives as cysteine protease inhibitors. PLoS One. 2013 Aug 5;8(8):e69982.

[2]. Toda G, et al. Calcium-activated neutral protease inhibitor (E-64c) and reperfusion for experimental myocardial infarction. Jpn Heart J. 1989 May;30(3):375-86.

[3]. Radzey H, et al. E-64c-hydrazide: a lead structure for the development of irreversible cathepsin C inhibitors. ChemMedChem. 2013 Aug;8(8):1314-21.

[相关活性小分子]

阿洛司他丁酸物理化学性质

[ 密度 ]:
1.2±0.1 g/cm3

[ 沸点 ]:
596.4±50.0 °C at 760 mmHg

[ 分子式 ]:
C₁₅H₂₆N₂O₅

[ 分子量 ]:
314.377

[ 闪点 ]:
314.5±30.1 °C

[ 精确质量 ]:
314.184174

[ PSA ]:
108.03000

[ LogP ]:
1.36

[ 蒸汽压 ]:
0.0±3.6 mmHg at 25°C

[ 折射率 ]:
1.504

[ 储存条件 ]:
−20°C

阿洛司他丁酸MSDS

详细MSDS(安全技术说明书)

阿洛司他丁酸毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: RR0404200

CHEMICAL NAME :: Oxiranecarboxylic acid, 3-(((3-methyl-1-(((3-methylbutyl)amino)carbonyl)butyl )amino) carbonyl)-, (2S-(2-alpha,3-beta(R*)))-

CAS REGISTRY NUMBER :: 76684-89-4

LAST UPDATED :: 199612

DATA ITEMS CITED :: 6

MOLECULAR FORMULA :: C15-H26-N2-O5

MOLECULAR WEIGHT :: 314.43

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 2140 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,736,1986

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: >1 gm/kg

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

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,736,1986

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

ROUTE OF EXPOSURE :: Intraperitoneal

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 2400 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Behavioral - ataxia Lungs, Thorax, or Respiration - dyspnea

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,736,1986

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

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: >1 gm/kg

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

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 17,736,1986 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 30 gm/kg/30D-C

TOXIC EFFECTS :: Liver - other changes Kidney, Ureter, Bladder - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 20,2001,1986

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 7500 mg/kg/30D-C

TOXIC EFFECTS :: Liver - other changes Kidney, Ureter, Bladder - other changes Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - transaminases

REFERENCE :: KSRNAM Kiso to Rinsho. Clinical Report. (Yubunsha Co., Ltd., 1-5, Kanda Suda-Cho, Chiyoda-ku, KS Bldg., Tokyo 101, Japan) V.1- 1960- Volume(issue)/page/year: 20,2001,1986

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阿洛司他丁酸安全信息

[ 个人防护装备 ]:
Eyeshields;Gloves;type N95 (US);type P1 (EN143) respirator filter

[ 危害码 (欧洲) ]:
Xi

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

[ WGK德国 ]:
3

[ RTECS号 ]:
RR0404200

阿洛司他丁酸合成路线

详细合成路线

阿洛司他丁酸文献

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Structural basis for development of cathepsin B-specific noncovalent-type inhibitor: crystal structure of cathepsin B-E64c complex.

Biochim. Biophys. Acta 1597(2) , 244-51, (2002)

In order to elucidate the substrate specificity of the Sn subsites (n=1-3) of cathepsin B, its crystal structure inhibited by E64c [(+)-(2S,3S)-3-(1-[N-(3-methylbutyl)amino]-leucylcarbonyl)oxirane-2-c...

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