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Squalene Synthase Inhibitors

Clinical Pharmacology and Cholesterol-Lowering Potential

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Abstract

HMG-CoA reductase inhibitors (statins) reduce cardiovascular disease morbidity and mortality with a high level of safety. Nonetheless, there are substantial numbers of people who either do not tolerate statins or whose low-density lipoprotein (LDL) levels are not lowered adequately. For these reasons, there is a need to develop other cholesterol-lowering drugs. A target for these new agents is provided by the enzymes distal to HMG-CoA reductase in the cholesterol biosynthesis pathway. Two classes of drugs have been developed: (i) squalene synthase inhibitors, which act at the first committed step in cholesterol biosynthesis, distal to the mevalonate-farnesyl diphosphate pathway; and (ii) oxidosqualene cyclase inhibitors, which act distal to the squalene intermediate. Of these, squalene synthase inhibitors have received more attention and are the subject of this review. Squalene synthase inhibitors decrease circulating LDL-cholesterol by the induction of hepatic LDL receptors in a similar manner to statins. They have fewer secondary effects mediated by a decrease in non-cholesterol products of mevalonate metabolism distal to HMG-CoA reductase, but have the potential to increase intermediates proximal to squalene. Squalene synthase inhibitors are just now entering clinical trials and data on how effectively they lower LDL-cholesterol and how they compliment the actions of statins and other agents is awaited with considerable interest.

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Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.

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  1. Division of Cardiovascular and Endocrine Sciences, Cardiovascular Research Group, University of Manchester, Core Technology Facility (3rd Floor), 46 Grafton Street, Manchester, M13 9NT, UK

    Valentine Charlton-Menys & Paul N. Durrington

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  1. Valentine Charlton-Menys
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  2. Paul N. Durrington
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Correspondence to Valentine Charlton-Menys.

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Charlton-Menys, V., Durrington, P.N. Squalene Synthase Inhibitors. Drugs 67, 11–16 (2007). https://doi.org/10.2165/00003495-200767010-00002

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