Kishida Y, Naito A, Iwado S, Terahara A, Tsujita Y
Research and Development Division, Tokyo, Japan.
Yakugaku Zasshi. 1991 Sep;111(9):469-87. doi: 10.1248/yakushi1947.111.9_469.
The attempts to find a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which catalyzes the rate limiting step of cholesterol biosynthesis were started from 1971. The first potent inhibitor, ML-236B (compactin), was found from the culture broth of Penicillium citrinum. Among many derivatives of ML-236B, pravastatin sodium (hereafter refer to pravastatin) was finally selected because of its potency and tissue selectivity. Since pravastatin has a hydroxyl group at 6 beta position in the skeleton of decaline of ML-236B, the microbial hydroxylation was adopted for the production of pravastatin. Streptomyces carbophilus was finally chosen as a potent converter with the formation of a lesser amount of by-products. For the sake of industrial production of pravastatin, many devices and improvements were performed for selecting high potent strains and for culturing conditions both with ML-236B and pravastatin. Pravastatin strongly inhibited the sterol synthesis in freshly isolated rat hepatocytes, but only weakly inhibited in the cells from nonhepatic tissues. This selective inhibition of pravastatin in sterol synthesis was further confirmed by ex vivo and in vivo experiments by using rats and mice. Pravastatin markedly reduced serum cholesterol levels in dogs, monkeys and rabbits, including Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. Pravastatin showed the preventive effect on the development of coronary atherosclerosis and xanthoma in young WHHL rabbits in consequence of maintaining the serum cholesterol levels low. In the clinical trials, pravastatin significantly reduced serum cholesterol and low density lipoprotein cholesterol levels, whereas inversely increased high density lipoprotein cholesterol levels.
寻找一种能有效抑制3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶的物质的尝试始于1971年，该酶催化胆固醇生物合成的限速步骤。第一种有效抑制剂ML-236B（洛伐他汀）是从桔青霉的培养液中发现的。在ML-236B的众多衍生物中，普伐他汀钠（以下简称普伐他汀）最终因其效力和组织选择性而被选中。由于普伐他汀在ML-236B的十氢化萘骨架的6β位有一个羟基，因此采用微生物羟基化法来生产普伐他汀。嗜碳链霉菌最终被选为一种有效的转化菌，其副产物生成量较少。为了实现普伐他汀的工业化生产，在选择高效菌株以及ML-236B和普伐他汀的培养条件方面进行了许多改进。普伐他汀强烈抑制新鲜分离的大鼠肝细胞中的固醇合成，但对非肝组织细胞的抑制作用较弱。通过对大鼠和小鼠进行的体外和体内实验进一步证实了普伐他汀在固醇合成中的这种选择性抑制作用。普伐他汀显著降低了狗、猴子和兔子的血清胆固醇水平，包括作为家族性高胆固醇血症动物模型的渡边遗传性高脂血症（WHHL）兔。由于维持了较低的血清胆固醇水平，普伐他汀对年轻的WHHL兔的冠状动脉粥样硬化和黄色瘤的发展显示出预防作用。在临床试验中，普伐他汀显著降低了血清胆固醇和低密度脂蛋白胆固醇水平，而高密度脂蛋白胆固醇水平则相反有所升高。
