YM‐53601, a novel squalene synthase inhibitor, reduces plasma cholesterol and triglyceride levels in several animal species

The aim of this study was to evaluate the potency of YM‐53601 (( E )‐2‐[2‐fluoro‐2‐(quinuclidin‐3‐ylidene) ethoxy]‐9 H ‐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 fibrates, respectively. 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 −1 ). In guinea‐pigs, YM‐53601 and pravastatin reduced plasma nonHDL‐C (=total cholesterol–high density lipoprotein cholesterol) by 47% ( P <0.001) and 33% ( P <0.001), respectively (100 mg kg −1 , daily for 14 days). In rhesus monkeys, YM‐53601 decreased plasma nonHDL‐C by 37% (50 mg kg −1 , twice daily for 21 days, P <0.01), whereas the HMG‐CoA reductase inhibitor, pravastatin, failed to do (25 mg kg −1 , twice daily for 28 days). YM‐53601 caused plasma triglyceride reduction in hamsters fed a normal diet (81% decrease at 50 mg kg −1 , daily for 5 days, P <0.001). In hamsters fed a high‐fat diet, the ability of YM‐53601 to lower triglyceride (by 73%, P <0.001) was superior to that of fenofibrate (by 53%, P <0.001), the most potent fibrate (dosage of each drug: 100 mg kg −1 , daily for 7 days). This is the first 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 fibrate in significantly lowering plasma triglyceride level. YM‐53601 may therefore prove useful in treating hypercholesterolemia and hypertriglyceridemia in humans.British Journal of Pharmacology (2000) 131 , 63–70; doi: 10.1038/sj.bjp.0703545