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Abstract: S4-4 ADVANCES IN SQUALENE SYNTHASE INHIBITORS
- Post-meeting symposia - Pharmacology and Atherosclerosis Abstract: S4-4 Citation: Atherosclerosis Supplement 2009, Vol. 10, Issue 2
ADVANCES IN SQUALENE SYNTHASE INHIBITORS M Davidson The University of Chicago Pritzker School of Medicine After formation of farnesyl pyrophosphate (farnesyl-PP) through a condensation process, squalene synthase catalyzes the head-to-tail condensation of two molecules of farnesyl-PP, yielding squalene. Squalene undergoes a 2-step cyclization to yield lanosterol. Through a series of 19 additional reactions, lanosterol is finally converted to cholesterol. Squalene synthase inhibitors would, therefore, decrease cholesterol synthesis without affecting the prenylated protein pathway, including ubiquinone, which is involved in muscle cell function. Squalene synthase catalysis is the first committed step of the de novo cholesterol biosynthetic pathway, and inhibition would avoid any potential adverse effect associated with reduced synthesis of the prenylated protein metabolites by the inhibitors of HMG CoA reductase. Therefore, squalene synthase inhibition was believed to have the potential to lower LDL to a similar degree as statins but avoid some of the potential side effects. The early squalene synthase inhibitors, such as zaragozic acids or squalene statins, were potent inhibitors of the enzyme but were either poorly bioavailable or were associated with significant toxicity. Other promising squalene synthase inhibitors were reported in the medical literature, such as RPR 107393, BMS-188494, ER27856, and YM-53601, but these compounds were not advanced into human trials. Most recently, lapaquistat, a novel squalene synthase was discontinued due to increased liver enzyme elevation.
ADVANCES IN SQUALENE SYNTHASE INHIBITORS M Davidson The University of Chicago Pritzker School of Medicine After formation of farnesyl pyrophosphate (farnesyl-PP) through a condensation process, squalene synthase catalyzes the head-to-tail condensation of two molecules of farnesyl-PP, yielding squalene. Squalene undergoes a 2-step cyclization to yield lanosterol. Through a series of 19 additional reactions, lanosterol is finally converted to cholesterol. Squalene synthase inhibitors would, therefore, decrease cholesterol synthesis without affecting the prenylated protein pathway, including ubiquinone, which is involved in muscle cell function. Squalene synthase catalysis is the first committed step of the de novo cholesterol biosynthetic pathway, and inhibition would avoid any potential adverse effect associated with reduced synthesis of the prenylated protein metabolites by the inhibitors of HMG CoA reductase. Therefore, squalene synthase inhibition was believed to have the potential to lower LDL to a similar degree as statins but avoid some of the potential side effects. The early squalene synthase inhibitors, such as zaragozic acids or squalene statins, were potent inhibitors of the enzyme but were either poorly bioavailable or were associated with significant toxicity. Other promising squalene synthase inhibitors were reported in the medical literature, such as RPR 107393, BMS-188494, ER27856, and YM-53601, but these compounds were not advanced into human trials. Most recently, lapaquistat, a novel squalene synthase was discontinued due to increased liver enzyme elevation.