INHIBITORS OF STEROL SYNTHESIS - EFFECTS OF A 7-ALPHA-ALKYL ANALOG OF3-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 r espect to its effects on HMG-CoA reductase activity in CHO-K1 cells an d on serum cholesterol levels in rats. The 7 alpha-methyl substitution had no detectable effect on the potency of I in lowering HMG-CoA redu ctase 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 low ering serum cholesterol levels in rats, it did so at dosage levels at which only slight or moderate effects on food consumption were observe d. Full H-1 and C-13-NMR assignments for II and intermediates in its s ynthesis have been presented. Conformational analysis, based on H-1-H- 1 coupling constants, NMR shieldings and force-field calculations, ind icated that the 7 alpha-methyl substitution had virtually no effect on the conformation of the 15-ketosterol apart from minor distortions of ring B.