INHIBITORS OF STEROL SYNTHESIS - METABOLISM-BASED DESIGN AND CONSTRUCTION OF A NEW ANALOG OF 3-BETA-HYDROXY-5-ALPHA-CHOLEST-8(14)-EN-15-ONEAND ITS EFFECTS IN CULTURED-MAMMALIAN-CELLS AND IN RATS

3 beta-Hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is a potent regulat or of cholesterol metabolism. In the present study, the 7 alpha-methyl -25,26,26,26,27,27,27-heptafluoro analog (X) of I has been synthesized with the goal of blocking not only the side chain oxidation of I but also its conversion to cholesterol. X was prepared in seven steps from the known 7 alpha-methyl analog (IX) of I. Treatment of the acetate o f IX with a mixture of trifluoroacetic anhydride, hydrogen peroxide, a nd sulfuric acid gave 3 beta-acetoxy-7 alpha-methyl-24-hydroxy-5 alpha -chol-8(14)-en-15-one (XII) in remarkably high (68%) yield. Dehydratio n of XII via the ortho-nitrophenylselenide to the 23-ene, followed by addition of (CF3)(2)CFI gave (23R)-3 beta-acetoxy-7 -methyl-23-iodo-25 ,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (XV). R eductive deiodination of XV with tributyltin hydride, followed by hydr olysis of the acetate gave 3 beta-hydroxy-7 alpha-methyl-25,26,26,26,2 7,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (X). The F-7-7 alp ha-methyl-15-ketosterol X lowered the levels of 3-hydroxy-3-methylglut aryl coenzyme A reductase activity in CHO-K1 cells with a potency equi valent to that of I. X showed significant hypocholesterolemic action u pon oral administration to rats, with a potency far in excess of the 7 alpha-methyl-15-ketosterol IX lacking the F-7 substitution. In marked contrast to I, X showed little or no suppression of food consumption in rats. Upon oral administration of X to rats, low levels of X (relat ive to cholesterol), characterized by chromatographic and gas chromato graphy-mass spectrometric methodologies, were observed in serum, liver , and small intestine. No material was observed with the expected prop erties of F-7-7-methylcholesterol (or potential intermediates in its p ossible formation from X). In contrast to I, X lowered serum cholester ol levels at dosages at which no effect on food consumption was observ ed.