lapaquistat

{{Short description|Chemical compound}}

{{Infobox drug

| Verifiedfields = changed

| verifiedrevid = 462088993

| 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

| image = Lapaquistat.svg

| tradename =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 189059-71-0

| ATC_prefix = none

| ATC_supplemental =

| PubChem = 9960389

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| ChemSpiderID = 8135996

| UNII_Ref = {{fdacite|correct|FDA}}

| UNII = PEZ79BV72X

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 341976

| C=31 | H=39 | Cl=1 | N=2 | O=8

| 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

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 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

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| StdInChIKey = HDGUKVZPMPJBFK-LEAFIULHSA-N

}}

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).{{cite journal | vauthors = Greenwood J, Steinman L, Zamvil SS | title = Statin therapy and autoimmune disease: from protein prenylation to immunomodulation | journal = Nature Reviews. Immunology | volume = 6 | issue = 5 | pages = 358–370 | date = May 2006 | pmid = 16639429 | pmc = 3842637 | doi = 10.1038/nri1839 }}

On March 28, 2008, Takeda halted further development of lapaquistat.{{cite web | url = http://www.takeda.com/press/article_29153.html | work = Takeda Pharmaceutical Company Limited press release | title = Discontinuation of Development of TAK-475, A Compound for Treatment of Hypercholesterolemia }} 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.{{cite journal | vauthors = Stein EA, Bays H, O'Brien D, Pedicano J, Piper E, Spezzi A | title = Lapaquistat acetate: development of a squalene synthase inhibitor for the treatment of hypercholesterolemia | journal = Circulation | volume = 123 | issue = 18 | pages = 1974–1985 | date = May 2011 | pmid = 21518985 | doi = 10.1161/CIRCULATIONAHA.110.975284 | doi-access = free }} 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,{{cite journal | vauthors = Nagashima S, Yagyu H, Tozawa R, Tazoe F, Takahashi M, Kitamine T, Yamamuro D, Sakai K, Sekiya M, Okazaki H, Osuga J, Honda A, Ishibashi S | display-authors = 6 | title = Plasma cholesterol-lowering and transient liver dysfunction in mice lacking squalene synthase in the liver | journal = Journal of Lipid Research | volume = 56 | issue = 5 | pages = 998–1005 | date = May 2015 | pmid = 25755092 | pmc = 4409289 | doi = 10.1194/jlr.M057406 |doi-access=free }} and efforts to mitigate this substrate accumulation would likely be necessary for clinical success of a squalene synthase inhibitor {{cite journal | vauthors = Wasko BM, Smits JP, Shull LW, Wiemer DF, Hohl RJ | title = A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro | journal = Journal of Lipid Research | volume = 52 | issue = 11 | pages = 1957–1964 | date = November 2011 | pmid = 21903868 | pmc = 3196227 | doi = 10.1194/jlr.M016089 |doi-access=free }}