STEROIDAL ETHERS - ANALOGS OF 7-KETOCHOLESTEROL

Several investigators have demonstrated that 7-ketocholesterol (1) inhibits β-hydroxy-β-methylglutaryl CoA reductase (EC 1.1.1.34) in vitro but not in vivo, presumably because of metabolic degradation. In an attempt to prepare analogues of 1 which might be more resistant to catabolism, a series of 7-ketocholesterol analogues having an oxygen atom in place of the carbon atoms at positions 20, 22, 23, and 24 of the cholesterol side chain has been synthesized. In addition, the corresponding analogues having a methyl group in place of the hydrogen atom at C-25 have also been prepared. One of the compounds, 7-keto-2I-nor-20-oxacholesterol (5b), has exhibited potent in vitro inhibition of HMG CoA reductase as well as inhibition of acyl coenzyme A/cholesterol acyltransferase (ACAT) (EC 2.3.1.26), an enzyme involved in the accumulation of cholesterol esters in the artery wall. However, 5b does not significantly inhibit HMG CoA reductase or lower serum cholesterol levels in rats when administered orally. © 1979, American Chemical Society. All rights reserved.