Inhibitors of sterol synthesis: effects of a 7 alpha-alkyl analog of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells and on serum cholesterol levels and other parameters in rats.

The 7 alpha-methyl analog (II) of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15- one (I) was prepared by chemical synthesis and evaluated with respect to its effects on HMG-CoA reductase activity in CHO-K1 cells and on serum cholesterol levels in rats. The 7 alpha-methyl substitution had no detectable effect on the potency of I in lowering HMG-CoA reductase activity in the cultured cells. In contrast, the 7 alpha-methyl substitution had a marked effect on the action of I in the suppression of food consumption in rats. Whereas II was less potent than I in lowering serum cholesterol levels in rats, it did so at dosage levels at which only slight or moderate effects on food consumption were observed. Full 1H and 13C-NMR assignments for II and intermediates in its synthesis have been presented. Conformational analysis, based on 1H-1H coupling constants, NMR shieldings and force-field calculations, indicated that the 7 alpha-methyl substitution had virtually no effect on the conformation of the 15-ketosterol apart from minor distortions of ring B.