Emerging lipid-lowering drugs: squalene synthase inhibitors.
BACKGROUND
Lapaquistat was the only squalene synthase inhibitor in Phase III clinical trials in Europe and the United States, but was recently discontinued from clinical development. Unlike statins, the inhibition of de novo cholesterol biosynthesis by lapaquistat does not deplete mevalonate, a precursor of isoprenoids. Isoprenoids are critical in cell growth and metabolism.


OBJECTIVE
The present review will focus on the chemistry, pharmacology, and lipid-lowering effects of novel squalene synthase inhibitors.


METHODS
A search of Pubmed, IPA, and GoogleScholar for studies (animal and human) and review articles published in English between 1990 and April 2008, using the search terms "squalene synthase inhibitors" or "lapaquistat". All clinical trials identified were then cross-referenced for their citations. All literature identified was then complied for this analysis.


CONCLUSIONS
Lapaquistat mainly targets LDL-C, but may have some effect on HDL-C and TG. Preliminary reports on Phase II and Phase III associated lapaquistat 100 mg with elevated hepatic enzymes. Hepatotoxicity, possible drug-drug interaction with statins, and the investigation of a statin/coenzyme Q10 combination are among the few challenges that impeded lapaquistat's clinical development.
University of Louisiana at Monroe, Department of Clinical and Administrative Sciences, College of Pharmacy, 700 University Avenue, Monroe, LA 71209, USA.
Raghda K
RK
Elsayed
Jeffery D
JD
Evans
D000818:Animals; D002318:Cardiovascular Diseases / Q000517:prevention & control; D002986:Clinical Trials as Topic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000009:adverse effects / Q000494:pharmacology*; D010077:Oxazepines / Q000009:adverse effects / Q000494:pharmacology; D010880:Piperidines / Q000009:adverse effects / Q000494:pharmacology
C466644:1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D010077:Oxazepines; D010880:Piperidines; D013186:Farnesyl-Diphosphate Farnesyltransferase