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.
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].
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