Cycloalkanones. 9. Comparison of analogs which inhibit cholesterol and fatty acid synthesis

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Abstract
A number of 2,8-dibenzylcyclooctanone analogs inhibited the HMG[3-hydroxymethylglutaryl]-CoA reductase activity of Holtzman male rat liver; only 2-octanone, 2-hexadecanone, 2,8-dibenzylcyclooctanone derivatives and 2-bis(4-chlorophenyl)-3,5-dimethyltetrahydro-4-pyrone inhibited fatty acid synthetase activity. 2-Octanone significantly lowered serum cholesterol, triglycerides, and glycerol levels in Holtzman male rats and serum cholesterol in male CF1 mice. Serum lipase activity was significantly elevated in rats administered 20 mg/kg per day of 2-octanone for 16 days. The activity of liver HMG-CoA reductase was inhibited in mice administered 10 mg/kg per day of 2-octanone for 10 days and in mouse and rat liver in vitro by 10 mg of 2-octanone. In mice, fecal excretion of [14C]cholesterol and tripalmitin was accelerated whereas palmitic acid and cholesteryl oleate were not affected by 10 mg/kg per day of 2-octanone. The LD50 in male mice for 2-octanone was 1.6 g/kg.