Lapaquistat

Lapaquistat

File:Lapaquistat.svg
Systematic (IUPAC) name
(1-{[(3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-(3-hydroxy-2,2-dimethylpropyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl]acetyl}piperidin-4-yl)acetic acid
Identifiers
CAS Number	189059-71-0 N
ATC code	none
PubChem	CID: 9960389
ChemSpider	8135996 Y
UNII	PEZ79BV72X Y
ChEMBL	CHEMBL341976 Y
Chemical data
Formula	C31H39ClN2O8
Molecular mass	603.103 g/mol
SMILES O=C(O)CC4CCN(C(=O)C[C@H]1O[C@@H](c2cc(Cl)ccc2N(C1=O)CC(C)(C)CO)c3cccc(OC)c3OC)CC4
InChI InChI=1S/C31H39ClN2O8/c1-31(2,18-35)17-34-23-9-8-20(32)15-22(23)28(21-6-5-7-24(40-3)29(21)41-4)42-25(30(34)39)16-26(36)33-12-10-19(11-13-33)14-27(37)38/h5-9,15,19,25,28,35H,10-14,16-18H2,1-4H3,(H,37,38)/t25-,28-/m1/s1 Y Key:HDGUKVZPMPJBFK-LEAFIULHSA-N Y
NY (what is this?)  (verify)

Lapaquistat (TAK-475) is a cholesterol-lowering drug. 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 over potential hepatic safety issues. Data 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