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

Abstract

The aim of this study was to evaluate the potency of YM-53601 ((E)-2-[2-fluoro-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 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.

Figure 1

Chemical structures of YM-53601 and FBQ.

Figure 2

In vivo inhibition of de novo cholesterol biosynthesis from acetate by YM-53601 in rats. Results are represented as mean±s.e.mean (n=4) of per cent inhibition versus the untreated control group. The ED₅₀ values for YM-53601 and FBQ of 32 mg kg⁻¹ and 18 mg kg⁻¹ respectively, were calculated by RS/1 program. The difference between these compounds was statistically significant by parallel line assay in the Statistical Analysis System (SAS).

Figure 3

Correlation between the percentage reduction in plasma nonHDL cholesterol and triglyceride in high-fat fed hamsters administered YM-53601 and fenofibrate. YM-53601; f(x)=1.24x–39.2, r²=0.6393 (P<0.001), fenofibrate; f(x)=−1.03x+59.7, r²=0.2976 (P<0.05). Data were taken from Table 5.

Figure 4

Time course for cholesterol lowering dose-dependent effects by YM-53601 in rhesus monkeys. Results are represented as mean±s.e.mean (n=5). Each compound was administered twice a day. R1 and R2 are the values for 1 and 2 weeks after the cessation of drug treatment, respectively. Statistical analysis versus control was carried out using Dunnett's multiple comparison test. ^*P<0.05, ^**P<0.01 versus control.

Figure 5

Time course for cholesterol lowering effects by YM-53601 and pravastatin in rhesus monkeys. Results are represented as mean±s.e.mean (n=5). Each compound was administered twice a day. R1 and R2 are the values for 1 and 2 weeks after the cessation of drug treatment, respectively. Statistical analysis was carried out using Dunnett's multiple comparison test versus control group in each week. ^*P<0.05 versus control. Resulted from two-way repeated ANOVA between YM-53601 at dose of 50 mg kg⁻¹ and pravastatin at dose of 25 mg kg⁻¹ about plasma total, nonHDL and HDL cholesterol levels for 4 weeks treatment, all parameters were statistically significant (P<0.001).