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.
Department of Biochemistry and Cell Biology, Rice University, Houston, Texas 77251-1892.
A U
AU
Siddiqui
N
N
Gerst
L J
LJ
Kim
F D
FD
Pinkerton
A
A
Kisic
W K
WK
Wilson
G J
GJ
Schroepfer
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D002783:Cholestenones / Q000138:chemical synthesis / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D006224:Cricetinae; D004435:Eating / Q000187:drug effects; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013261:Sterols / Q000096:biosynthesis* / Q000097:blood; D013329:Structure-Activity Relationship
D002783:Cholestenones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; C015073:cholest-8(14)-en-3-ol-15-one; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases