| dbo:abstract |
Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed. Unlike statins, which inhibit HMG-CoA reductase, lapaquistat metabolites inhibit squalene synthase, which is further downstream in the synthesis of cholesterol. It is hoped that side effects can be reduced by not disturbing the mevalonate pathway, which is important for other biochemical molecules besides cholesterol.However, there is increasing evidence that statins (which inhibit the mevalonate pathway) may be clinically useful because they affect these other molecules (including protein prenylation). On March 28, 2008, Takeda halted further development of lapaquistat. While effective at lowering low-density lipoprotein cholesterol in a dose-dependent manner, development of the drug was ceased due to observations in clinical trials that it might cause liver damage in the high dose trial groups. Data from knockout mouse studies suggests that accumulation of high levels of the metabolic substrate of squalene synthase and derivatives thereof account for the liver toxicity of squalene synthase inhibitors, and efforts to mitigate this substrate accumulation would likely be necessary for clinical success of a squalene synthase inhibitor (en) ラパキスタット（Lapaquistat）はコレステロール低下作用を期待してかつて開発されていた化合物である。HMG-CoAレダクターゼを阻害するスタチンと異なり、ラパキスタットは下流のを阻害するのでメバロン酸経路を乱さないことから、副作用が低減することを見込まれていた。しかし、スタチン（メバロン酸経路を阻害する）が他の関連分子にも影響（蛋白質のプレニル化過程を含む）を与える事が臨床的に有用であることが明らかとなって来た。 2008年3月、安全性・有効性の両面から既存の医薬品に勝る点がないとしてラパキスタットの開発は中止された。開発コードTAK-475。 (ja) |
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341976 |
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9960389 |
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| gold:hypernym |
dbr:Drug |
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| rdfs:comment |
ラパキスタット（Lapaquistat）はコレステロール低下作用を期待してかつて開発されていた化合物である。HMG-CoAレダクターゼを阻害するスタチンと異なり、ラパキスタットは下流のを阻害するのでメバロン酸経路を乱さないことから、副作用が低減することを見込まれていた。しかし、スタチン（メバロン酸経路を阻害する）が他の関連分子にも影響（蛋白質のプレニル化過程を含む）を与える事が臨床的に有用であることが明らかとなって来た。 2008年3月、安全性・有効性の両面から既存の医薬品に勝る点がないとしてラパキスタットの開発は中止された。開発コードTAK-475。 (ja) Lapaquistat (TAK-475) is a cholesterol-lowering drug candidate that was abandoned before being marketed. Unlike statins, which inhibit HMG-CoA reductase, lapaquistat metabolites inhibit squalene synthase, which is further downstream in the synthesis of cholesterol. It is hoped that side effects can be reduced by not disturbing the mevalonate pathway, which is important for other biochemical molecules besides cholesterol.However, there is increasing evidence that statins (which inhibit the mevalonate pathway) may be clinically useful because they affect these other molecules (including protein prenylation). (en) |
| rdfs:label |
Lapaquistat (en) ラパキスタット (ja) |
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