Current Atherosclerosis Reports

, Volume 9, Issue 1, pp 78–80

Squalene synthase inhibition: A novel target for the management of dyslipidemia

Article

Abstract

A new class of compounds, known as squalene synthase inhibitors, has recently reached phase III clinical trials and may provide another therapeutic option for clinicians to improve risk management of low-density lipoprotein cholesterol (LDL-C). The clinical need for another LDL-C-lowering therapy is evident by the inability to achieve an LDL-C target of less than 70 mg/dL in the majority of very high-risk patients on statin monotherapy. Human clinical trial data with TAK-475, a novel and potent inhibitor of squalene synthase, have not yet been published.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Grundy SM, Cleeman JI, Merz CN, et al.; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association: Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004, 110:227–239.PubMedCrossRefGoogle Scholar
  2. 2.
    Smith SC Jr, Allen J, Blair SN, et al.; AHA/ACC; National Heart, Lung, and Blood Institute: AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006, 113:2363–2372.PubMedCrossRefGoogle Scholar
  3. 3.
    LaRosa JC, Grundy SM, Waters DD, et al.; Treating to New Targets (TNT) Investigators: Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005, 352:1425–1435.PubMedCrossRefGoogle Scholar
  4. 4.
    Pedersen TR, Faergeman O, Kastelein JJ, et al.; Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group: High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA 2005, 294:2437–2445.PubMedCrossRefGoogle Scholar
  5. 5.
    Davidson MH, Maki KC, Pearson TA, et al.: Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations. Am J Cardiol 2005, 96:556–563.PubMedCrossRefGoogle Scholar
  6. 6.
    Nissen SE, Nicholls SJ, Sipahi I, et al.: ASTEROID Investigators: Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006, 295:1556–1565.PubMedCrossRefGoogle Scholar
  7. 7.
    Robinson JG, Davidson MH: Combination therapy with ezetimibe and simvastatin to achieve aggressive LDL reduction. Expert Rev Cardiovasc Ther 2006, 4:461–476.PubMedCrossRefGoogle Scholar
  8. 8.
    Davidson MH, Robinson JG: Lipid-lowering effects of statins: a comparative review. Expert Opin Pharmacother 2006, 7:1701–1714.PubMedCrossRefGoogle Scholar
  9. 9.
    Soma MR, Corsini A, Paoletti R: Cholesterol and mevalonic acid modulation in cell metabolism and multiplication. Toxicol Lett 1992, 64–65(Spec No):1–15.PubMedCrossRefGoogle Scholar
  10. 10.
    Eggens I, Eriksson LC, Chojnacki T, Dallner G: Role of dolichyl phosphate in regulation of protein glycosylation in 2-acetylaminofluorene-induced carcinogenesis in rat liver. Cancer Res 1984, 44:799–805.PubMedGoogle Scholar
  11. 11.
    Davignon J: Beneficial cardiovascular pleiotropic effects of statins. Circulation 2004, 109(23 Suppl 1):III39–43.PubMedGoogle Scholar
  12. 12.
    Hargreaves IP, Duncan AJ, Heales SJ, Land JM: The effect of HMG-CoA reductase inhibitors on coenzyme Q10: possible biochemical/clinical implications. Drug Safety 2005, 28:659–676.PubMedCrossRefGoogle Scholar
  13. 13.
    Lamperti C, Naini AB, Lucchini V, et al.: Muscle coenzyme Q10 level in statin-related myopathy. Arch Neurol 2005, 62:1709–1712.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakamura S: Total synthesis of the squalene synthase inhibitor zaragozic acid C. Chem Pharm Bull (Tokyo) 2005, 53:1–10.CrossRefGoogle Scholar
  15. 15.
    Amin D, Rutledge RZ, Needle SN, et al.: RPR 107393, a potent squalene synthase inhibitor and orally effective cholesterollowering agent: comparison with inhibitors of HMG-CoA reductase. J Pharmacol Exp Ther 1997, 281:746–752.PubMedGoogle Scholar
  16. 16.
    Sharma A, Slugg PH, Hammett JL, Jusko WJ: Clinical pharmacokinetics and pharmacodynamics of a new squalene synthase inhibitor, BMS-188494, in healthy volunteers. J Clin Pharmacol 1998, 38:1116–1121.PubMedGoogle Scholar
  17. 17.
    Hiyoshi H, Yanagimachi M, Ito M, et al.: Effect of ER-27856, a novel squalene synthase inhibitor, on plasma cholesterol in rhesus monkeys: comparison with 3-hydroxy-3-methylglutaryl-coa reductase inhibitors. J Lipid Res 2000, 41:1136–1144.PubMedGoogle Scholar
  18. 18.
    Ugawa T, Kakuta H, Moritani H, et al.: YM-53601, a novel squalene synthase inhibitor, suppresses lipogenic biosynthesis and lipid secretion in rodents. Br J Pharmacol 2003, 139:140–146.PubMedCrossRefGoogle Scholar
  19. 19.
    Miki T, Kori M, Mabuchi H, et al.: Synthesis of novel 4,1-benzoxazepine derivatives as squalene synthase inhibitors and their inhibition of cholesterol synthesis. J Med Chem 2002, 45:4571–4580.PubMedCrossRefGoogle Scholar
  20. 20.
    Amano Y, Nishimoto T, Tozawa R, et al.: Lipid-lowering effects of TAK-475, a squalene synthase inhibitor, in animal models of familial hypercholesterolemia. Eur J Pharmacol 2003, 466:155–161.PubMedCrossRefGoogle Scholar
  21. 21.
    Nishimoto T, Tozawa R, Amano Y, et al.: Comparing myotoxic effects of squalene synthase inhibitor, T-91485, and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in human myocytes. Biochem Pharmacol 2003, 66:2133–2139.PubMedCrossRefGoogle Scholar
  22. 22.
    Clinical Trials Database. Available at http://www.clinicaltrials.gov. Accessed September 5, 2006.Google Scholar

Copyright information

© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Radiant ResearchChicagoUSA

Personalised recommendations