22-Hydroxycholesterol Derivatives as HMG CoA Reductase Suppressors and Serum Cholesterol Lowering Agents

Article abstract of DOI:10.1021/jm00380a008

A series of 22-hydroxycholesterol derivatives with a modified side chain terminus was prepared.These agents were evaluated in vitro and in vivo for their ability to suppress HMG CoA reductase, the rate-limiting enzyme of cholesterol biosynthesis.In tissue culture assays, 22-hydroxycholesterol as well as the side chain modified analogues were potent inhibitors of HMG CoA reductase.However, only those sterols with a modified side chain terminus were effective suppressors of liver reductase whene administered ig to rats. 22-Hydroxy-25-methylcholesterol (4a) and 25-fluoro-22-hydroxycholesterol (15a) significantly lowered serum cholesterol levels when administered ig to primates; 25-chloro-22-hydroxycholesterol (15b) and the analogue with a cyclopropyl terminus, 20b, were ineffective.The cholesterol-lowering sterols did not significantly alter lipoprotein levels; however, the two compounds have been shown to inhibit acyl-coenzyme A:cholesterol-transferase (ACAT) in tissue culture studies