MEVINOLIN - A HIGHLY POTENT COMPETITIVE INHIBITOR OF HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE AND A CHOLESTEROL-LOWERING AGENT
MEVINOLIN - A HIGHLY POTENT COMPETITIVE INHIBITOR OF HYDROXYMETHYLGLUTARYL-COENZYME-A REDUCTASE AND A CHOLESTEROL-LOWERING AGENT
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DOI：
10.1073/pnas.77.7.3957
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发表时间：
1980-01-01
期刊：
影响因子：
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通讯作者：
SPRINGER, J
中科院分区：
文献类型：
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作者：
ALBERTS, AW;CHEN, J;SPRINGER, J
从土曲霉的培养物中分离出一种真菌代谢产物Mevinolin。mevinolin及其开放酸形式mevinolinic酸的结构和绝对构型由物理技术的组合确定。Mevinolin是1，2，6，7，8，8 α-六氢-β，.三角洲-二羟基-2，6-二甲基-8-（2-甲基-1-氧代丁氧基）-1-萘-庚酸δ-内酯。羟基酸形式的美维诺林（美维诺林酸）是3-羟基-3-甲基戊二酰-辅酶A还原酶[甲羟戊酸：NADP+氧化还原酶（CoA-酰化），EC 1.1.1.34]的强效竞争性抑制剂;其Ki [抑制常数]为0.6 nM，与先前描述的相关抑制剂ML-236 B（美伐他汀，6-去甲基美维诺林）的羟基酸形式的Ki [抑制常数]为1.4 nM相比。在大鼠中，口服给予的美维诺林钠在急性试验中是胆固醇合成的活性抑制剂（50%抑制剂量= 46 μ g/kg）。Mevinolin是一种口服活性降胆固醇药物。用mevinolin以8 mg/kg/天治疗狗3周，引起29.3 ± 0.01 mg/kg/天。血浆胆固醇降低2.5%。Mevinolin可用于治疗高胆固醇血症，高胆固醇血症是人类冠状动脉疾病的主要危险因素。
Mevinolin, a fungal metabolite, was isolated from cultures of Aspergillus terreus. The structure and absolute configuration of mevinolin and its open acid form, mevinolinic acid, were determined by a combination of physical techniques. Mevinolin was 1,2,6,7,8,8a-hexahydro-.beta.,.delta.-dihydroxy-2,6-dimethyl-8-(2-methyl-1-oxobutoxy)-1-naphthalene-heptanoic acid .delta.-lactone. Mevinolin in the hydroxy acid form, mevinolinic acid, is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34]; its Ki [inhibition constant] of 0.6 nM can be compared to 1.4 nM for the hydroxy acid form of the previously described related inhibitor, ML-236B (compactin, 6-demethylmevinolin). In the rat, orally administered sodium mevinolinate was an active inhibitor of cholesterol synthesis in an acute assay (50% inhibitory dose = 46 .mu.g/kg). Mevinolin was an orally active cholesterol-lowering agent in the dog. Treatment of dogs for 3 wk with mevinolin at 8 mg/kg per day caused a 29.3 .+-. 2.5% lowering of plasma cholesterol. Mevinolin may be used to treat hypercholesterolemia a primary risk factor for coronary artery disease in man.