1 The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-¯uoro-2-(quinuclidin-3-ylidene) ethoxy]-9H-carbazole monohydrochloride), a new inhibitor of squalene synthase, in reducing both plasma cholesterol and triglyceride levels, compared with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor and ®brates, respectively. 2 YM-53601 equally inhibited squalene synthase activities in hepatic microsomes prepared from several animal species and also suppressed cholesterol biosynthesis in rats (ED 50 , 32 mg kg 71 ). 3 In guinea-pigs, YM-53601 and pravastatin reduced plasma nonHDL-C (=total cholesterol ± high density lipoprotein cholesterol) by 47% (P50.001) and 33% (P50.001), respectively (100 mg kg 71 , daily for 14 days). In rhesus monkeys, YM-53601 decreased plasma nonHDL-C by 37% (50 mg kg 71, twice daily for 21 days, P50.01), whereas the HMG-CoA reductase inhibitor, pravastatin, failed to do (25 mg kg 71 , twice daily for 28 days). 4 YM-53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg 71 , daily for 5 days, P50.001). In hamsters fed a high-fat diet, the ability of YM-53601 to lower triglyceride (by 73%, P50.001) was superior to that of feno®brate (by 53%, P50.001), the most potent ®brate (dosage of each drug: 100 mg kg 71, daily for 7 days). 5 This is the ®rst report that a squalene synthase inhibitor is superior to an HMG-CoA reductase inhibitor in lowering plasma nonHDL-C level in rhesus monkeys and is superior to a ®brate in signi®cantly lowering plasma triglyceride level. YM-53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.

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