32-Methyl-32-oxylanosterols: dual-action inhibitors of cholesterol biosynthesis.
Lanosterol 14 alpha-methyl demethylase (P-450DM) is the cytochrome P-450 monooxygenase which oxidatively removes the 14 alpha-methyl group of lanosterol. This demethylation is considered to be a rate-limiting step in the conversion of lanosterol to cholesterol. The intermediates in this transformation are known to bind very tightly to P-450DM and have been implicated in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) activity, the rate-limiting enzyme in overall cholesterol biosynthesis. Three 32-methylated analogs of the intermediates generated during the removal of the 14 alpha-methyl group by P-450DM, compounds 17a, 17b, and 18, have been prepared and their biochemical activities assessed. All three compounds were found to be direct inhibitors of P-450DM. These compounds were also shown to suppress HMGR activity by reducing the level of enzyme protein.
Frye
L L
LL
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590.
Cusack
K P
KP
Leonard
D A
DA
D000818:Animals; D016466:CHO Cells; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D015195:Drug Design; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D066298:In Vitro Techniques; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000138:chemical synthesis* / Q000494:pharmacology*
D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; D002784:Cholesterol; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase