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CAS No.: 591778-70-0

CP-640186 HCl Catalog No. CSN18348

Synonyms: CP-640186;CP-640,186

CP-640186 HCl is a metabolic stability improved ACC inhibitor with IC50 values of 53 nM and 61 nM for rat liver ACC1 and rat skeletal muscle ACC2,respectively.

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靶点选择性

生物活性

实验方案

技术信息

生物活性

描述Acetyl-coenzyme A carboxylases (ACCs) are crucial for the metabolism of fatty acids and are promising targets for drug, such as CP-640186 Hydrochloride, development against obesity, diabetes, and other diseases. ACCs catalyzes the conversion of acetyl-CoA to malonyl-CoA. CP-640186 is a novel isozyme-nonselective inhibitor of mammalian ACCs with IC₅₀ values of about 50 nM, including two isoforms of mammalian ACCs and can reduce body weight and improve insulin sensitivity in test animals. It is believed to target the carboxyltransferase (CT) domain of enzymes^[3]. Inhibition that induced by CP-640186 hydrochloride was reversible, uncompetitive with respect to ATP, and non-competitive with respect to bicarbonate, acetyl-CoA, and citrate, indicating interaction with the enzymatic carboxyl transfer reaction. In a vitro study, CP-640186 hydrochloride inhibited both rat liver ACC1 and rat skeletal muscle ACC2 with IC₅₀ 53 nM and 61 nM, respectively. In a vivo study, mice were given food and water which were treated at a volume of 0.25 ml/25 g of body weight with an aqueous solution containing 0.5% methyl cellulose plus CP-640186 hydrochloride. 1 to 4h after CP-640186 hydrochloride administration, mice were injected with 0.2 ml of [2-¹⁴C]acetate then radiolabel test was performed, suggesting that hepatic fatty acid synthesis was inhibited by CP-640186 hydrochloride. Single-dose oral treatment with 100 mg/kg CP-640186 also reduced tissue malonyl-CoA concentrations in chow-fed animals such that liver levels were reduced by 58%, heart levels were reduced by 63%, soleus muscle levels were reduced by 59%, and quadriceps muscle levels were reduced by 80% within 1h of administration^[4].
作用机制CP-640186 hydrochloride is bound in the active site at the interface of a dimer of the carboxyltransferase domain. In other words, CP-640186 hydrochloride has tight interactions with the biotin binding site in the carboxyltransferase domain and three regions for CP-640186 hydrochloride binding in the active site of carboxyltransferase^[3].

动物研究

剂量

Rat: 4 mg/kg^[2] (i.v.); 10 mg/kg^[2] (p.o.) Mice: 10 mg/kg - 100 mg/kg^[2] (i.p.)

给药途径

i.v., p.o., i.p.

动物药代数据

Animal	Mice^[2]	Rats^[2]
Dose	5 mg/kg (i.v.) 10 mg/kg (p.o.)	5 mg/kg (i.v.) 10 mg/kg (p.o.)
Administration	i.v. p.o.	i.v. p.o.
F	0.5	0.39
T_1/2	1.1 h	1.5 h
T_max	0.25 h (p.o.)	1.0 h (p.o.)
CL_p		65 ml/min/kg
C_max	2177 ng/ml (p.o.)	345 ng/ml (p.o.)
Vd_ss		5 L/kg
AUC_0→∞	3068 ng·h/ml (p.o.)	960 ng·h/ml (p.o.)

参考文献

[1] Zhang H, Tweel B, et al. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure. 2004 Sep;12(9):1683-91.
[2] Harwood HJ Jr, Petras SF, et al. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 2003 Sep 26;278(39):37099-111.
[3] Zhang H, Tweel B, Li J, Tong L. Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186. Structure. 2004 Sep;12(9):1683-91.
[4] Harwood HJ Jr, Petras SF, Shelly LD, Zaccaro LM, Perry DA, Makowski MR, Hargrove DM, Martin KA, Tracey WR, Chapman JG, Magee WP, Dalvie DK, Soliman VF, Martin WH, Mularski CJ, Eisenbeis SA. Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations, inhibit fatty acid synthesis, and increase fatty acid oxidation in cultured cells and in experimental animals. J Biol Chem. 2003 Sep 26;278(39):37099-111.

实验方案

计算器摩尔计算器总药量计算器工作液计算器
储存液制备
- 1 mg
- 5 mg
- 10 mg
- 1 mM
- 1.9154 mL
- 9.5771 mL
- 19.1542 mL
- 5 mM
- 0.3831 mL
- 1.9154 mL
- 3.8308 mL
- 10 mM
- 0.1915 mL
- 0.9577 mL
- 1.9154 mL

技术信息

CAS号

591778-70-0

储存条件

粉末: Keep in dark place,Inert atmosphere,Room temperature

液体: -20°C:3-6 月 -80°C:12月

分子式

C30H36ClN3O3

运输

蓝冰

分子量

522.08

别名

CP-640186;CP-640,186

溶解度

DMSO	210.0 mg/mL (402.2 mM)
Water	120.0 mg/mL (229.9 mM)

动物实验配方

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