A prodrug form of ETC-1002-CoA
ETC-1002 is a prodrug form of ETC-1002-CoA.1 ETC-1002 is conjugated to coenzyme A (CoA) by very long-chain acyl-CoA synthetase-1 (ACSVL1) to form ETC-1002-CoA, which inhibits ATP citrate lyase (Ki = 2 μM) and activates AMP-activated protein kinase (AMPK). ETC-1002 suppresses total lipid synthesis in wild-type and AMPKβ1 knockout primary murine hepatocytes. In vivo, ETC-1002 (30 mg/kg) prevents increases in hepatic cholesterol and reduces the size of aortic atherosclerotic lesions induced by a high-fat high-cholesterol diet in Apoe-/-/Ampkβ1-/- (DKO) mice.
1.Pinkosky, S.L., Newton, R.S., Day, E.A., et al.Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosisNat. Commun.7:13457(2016)
|
Cell experiment: |
Glucose production is measured in primary rat hepatocyte cultures. Cells are cultured in glucose- and phenol red-free DMEM, containing 10 mM lactate, 1 mM pyruvate, and nonessential amino acids. Cells are incubated with various concentrations of Bempedoic acid (0.1 to 100 μM)[1]. |
|
Animal experiment: |
Rats: Prior to single-dose Bempedoic acid administration, Male Wistar Han rats are fasted for 48 h and refed a high-carbohydrate diet for an additional 48 h. For two-week assessment, rats are maintained on standard chow diet and dosed by oral gavage with Bempedoic acid at 30 mg/kg/day for two weeks in the morning. Following nutritional staging and/or dosing, food is withdrawn 2 h prior to last the oral dose of ehicle control or Bempedoic acid[1]. |
|
参考文献: [1]. Pinkosky SL, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013 Jan;54(1):134-51. |
|
动态评分
0.0