首页
按字顺浏览
期刊浏览
卷期浏览
RG 12561 (Dalvastatin): A Novel Synthetic Inhibitor of HMG-CoA Reductase and Cholestero...
|
RG 12561 (Dalvastatin): A Novel Synthetic Inhibitor of HMG-CoA Reductase and Cholesterol-Lowering Agent
作者:
Dilip Amin,
Susan Gustafson,
Judith M. Weinacht,
Susan A. Cornell,
Kent Neuenschwander,
Benedict Kosmider,
Anthony C. Scotese,
John R. Regan,
Mark H. Perrone,
期刊:
Pharmacology
(Karger Available online 1993)
卷期:
Volume 46,
issue 1
页码: 13-22
ISSN:0031-7012
年代: 1993
DOI:10.1159/000139024
出版商: S. Karger AG
关键词: HMG-CoA reductase;RG 12561;Dalvastatin;Lovastatin;Pravastatin;Cholesterol
数据来源: Karger
摘要:
RG 12561 (dalvastatin) is a prodrug which converts to its open hydroxyacid form in the body. The Na salt of RG 12561 (RG 12561-Na) is a potent inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway. It competitively inhibits rat liver HMG-CoA reductase with an IC50 value of 3.4 nmol/l. In the same assay, the IC50 values for other potent HMG-CoA reductase inhibitors, lovastatin-Na and pravastatin, were 2.3 and 8.9 nmol/l, respectively. In Hep G2 liver cells, RG 12561-Na, lovastatin-Na and pravastatin inhibited cholesterol biosynthesis from radiolabeled octanoate with IC50 values of 4 and 5 nmol/l and 1.1 μmol/l, respectively. In a rat ex vivo assay, orally administered RG 12561 lovastatin and pravastatin inhibited cholesterol biosynthesis in liver slices with ED50 values of 0.9, 0.5 and 12 mg/kg, respectively. In cholestyramine-fed hamsters, RG 12561 (0.1% in food for 18 days) reduced LDL cholesterol, whereas HDL was slightly increased. The reductions in the LDL/HDL ratio for RG 12561, RG 12561-Na, lovastatin and lovastatin-Na were 35, 76, 88 and 88%, respectively. At a higher dose, RG 12561 (0.4% in food) reduced serum cholesterol, LDL and LDL/HDL by 84, 97 and 91 %, respectively. In WHHL rabbits, RG 12561 and lovastatin (5 mg/kg, b.i.d., 12 days) reduced serum cholesterol by 17 and 16 %, respectively. These results demonstrate that RG 12561 is a potent cholesterol-lowering agent
点击下载:
PDF
(1742KB)
返 回
|
|