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Farnesyl diphosphate, the substrate for squalene synthase, accumulates in the presence of zaragozic acid A, a squalene synthase inhibitor. A possible metabolic fate for farnesyl diphosphate is its conversion to farnesol, then to farnesoic acid, and finally to farnesol-derived dicarboxylic acids (FDDCAs) which would then be excreted in the urine. Seven dicarboxylic acids were isolated by high performance liquid chromatography (HPLC) from urine of either rats or dogs treated with zaragozic acid A or rats fed farnesol. Their structures were determined by nuclear magnetic resonance analysis. Two 12-carbon, four 10-carbon, and one 7-carbon FDDCA were identified. The profile of urinary dicarboxylic acids from rats fed farnesol was virtually identical to that produced by treating with zaragozic acid A, establishing that these dicarboxylic acids are farnesolderived. By feeding [1-14 C]farnesol and comparing the mass of the dicarboxylic acids produced with the ultraviolet absorption of the HPLC peaks, a method to quantitate the ultraviolet-absorbing FDDCAs was devised. When rats were treated with zaragozic acid A, large amounts of FDDCAs were excreted in the urine. The high level of FDDCAs that were found suggests that their synthesis is the major metabolic fate for carbon diverted from cholesterol synthesis by a squalene synthase inhibitor. A metabolic pathway is proposed to explain the production of each of these FDDCAs.Squalene synthase is an attractive target for the development of a cholesterol synthesis inhibitor that could serve as a cholesterol lowering agent. Cholesterol synthesis inhibitors, such as lovastatin (1), a 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor, are effective cholesterol-lowering agents in man and/or animals. Squalene synthase catalyzes the first committed step in cholesterol synthesis, and selective inhibition of this enzyme should result in inhibition of cholesterol synthesis without affecting the synthesis of other isoprenoids such as dolichol, ubiquinone, and the prenylated proteins. A novel class of fungal metabolites, known as zaragozic acids, has been recently discovered and characterized as potent inhibitors of squalene synthase (2-8). The zaragozic acids are subnanomolar inhibitors of squalene synthase in vitro, they inhibit cholesterol synthesis from acetate or mevalonate in cell culture and in animal models, and also have been shown to lower plasma cholesterol when administered orally in certain animal species (4, 5,8). Other classes of squalene synthase inhibitors have also been discovered (for a review, see Ref. 9).An important question to be answered for these compounds is the metabolic effect of inhibition of squalene synthase. The squalene synthase reaction consists of the reductive dimerization of two molecules of farnesyl diphosphate (FPP) 1 to form a molecule of squalene (10). The primary consequence of inhibition of this reaction would be an accumulation of FPP. Thus, the metabolic fate of FPP in the presence of a squalene synthase inhibitor is of interest. Previous wor...

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Anacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has previously been shown to reduce low-density lipoprotein cholesterol (LDL-C) and raise high-density lipoprotein cholesterol (HDL-C) in patients with or at high risk of coronary heart disease in the 76-week, placebo-controlled, Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) trial. Here, we report the results of the 2-year extension to the DEFINE study where patients (n = 803) continued on the same assigned treatment as in the original 76-week study. Treatment with anacetrapib during the 2-year extension was well tolerated with a safety profile similar to patients on placebo. No clinically important abnormalities in liver enzymes, blood pressure, electrolytes, or adverse experiences were observed during the extension. At the end of the extension study, relative to the original baseline value, anacetrapib reduced Friedewald-calculated LDL-C by 39.9% and increased HDL-C by 153.3%, compared to placebo. The apparent steady state mean plasma trough concentration of anacetrapib was ∼640 nmol/L. Geometric mean plasma concentrations of anacetrapib did not appear to increase beyond week 40 of the 2-year extension of the 76-week DEFINE base study. In conclusion, an additional 2 years of treatment with anacetrapib were well tolerated with durable lipid-modifying effects on LDL-C and HDL-C.