プラバスタチンの開発研究
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概要
- 論文の詳細を見る
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 6β 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.
- 社団法人日本薬学会の論文
- 1991-09-25
著者
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内藤 敦
八尾市立病院外科
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内藤 敦
三共(株)
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内藤 敦
三共株式会社
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寺原 昭
医薬開発第二部
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岸田 有吉
三共株式会社研究開発本部
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内藤 敦
田無工場
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岩藤 誠吾
醗酵研究所
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辻田 代史雄
醗酵研究所
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岸田 有吉
三共株式会社中央研究所
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