Lapaquistat (TAK-475) is a

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

-lowering drug candidate that was abandoned before being marketed. Unlike statins, which inhibit

HMG-CoA reductase HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, official symbol HMGCR) is the rate-controlling enzyme (NADH-dependent, ; NADPH-dependent, ) of the mevalonate pathway, the metabolic pathway that produces cholesterol and oth ...

, lapaquistat metabolites inhibit

squalene synthase Squalene synthase (SQS) or farnesyl-diphosphate:farnesyl-diphosphate farnesyl transferase is an enzyme localized to the membrane of the endoplasmic reticulum. SQS participates in the isoprenoid biosynthetic pathway, catalyzing a two-step react ...

, 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 Prenylation (also known as isoprenylation or lipidation) is the addition of hydrophobic molecules to a protein or a biomolecule. It is usually assumed that prenyl groups (3-methylbut-2-en-1-yl) facilitate attachment to cell membranes, similar to ...

). 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 A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or "knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

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

References

Further reading