Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.
Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.
Department of Internal Medicine, University of Colorado Health Science Center, Denver, USA.
Stephanie
S
Seiki
William H
WH
Frishman
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002784:Cholesterol / Q000378:metabolism*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D010077:Oxazepines / Q000627:therapeutic use*; D010880:Piperidines / Q000627:therapeutic use*; D013185:Squalene / Q000031:analogs & derivatives / Q000378:metabolism
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; D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010077:Oxazepines; D010880:Piperidines; C520393:oxidosqualene; D013185:Squalene; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase