title: Substrate-based inhibitors of lanosterol 14 alpha-methyl demethylase: I. Assessment of inhibitor structure-activity relationship and cholesterol biosynthesis inhibition properties.
abstract: A series of 15-, 32-, and 15,32-substituted lanost-8-en-3 beta-ols is described which function as inhibitors of cholesterol biosynthesis. These agents inhibit lanosterol 14 alpha-methyl demethylase activity as well as suppress HMG-CoA reduction activity in cultured cells. Several of these agents are extremely potent as both demethylase inhibitors and reductase suppressors, while others are more selective in their activities. Selected regio double bond isomers show preference for demethylase inhibition with the following order: delta 8 > delta 7 > delta 6 = unsaturated sterols. Comparisons also show that 4,4-dimethyl sterols are always more potent demethylase inhibitors and reductase suppressors than their 4,4-bisnomethyl counterparts. However, evaluation of an extensive oxylanosterol series leads us to conclude that demethylase inhibition and reductase suppression are not parallel in the same molecule. In addition, the oxylanosterols, but not the oxycholesterols, are able to disrupt coordinate regulation of HMG-CoA reductase from the LDL receptor. Thus, oxylanosterol treatment at levels which suppress reductase activity enhances LDL receptor activity. These results demonstrate that compounds can be made which (1) are selective reductase suppressors enabling dissection of the dual inhibitor nature of these compounds and (2) maximize reductase suppression and LDL receptor induction without demethylase inhibition which could lead to novel agents for serum cholesterol lowering.
authors.affiliation: Du Pont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0400, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Trzaskos
authors.forename: S S
authors.initials: SS
authors.lastname: Ko
authors.forename: R L
authors.initials: RL
authors.lastname: Magolda
authors.forename: M F
authors.initials: MF
authors.lastname: Favata
authors.forename: R T
authors.initials: RT
authors.lastname: Fischer
authors.forename: S H
authors.initials: SH
authors.lastname: Stam
authors.forename: P R
authors.initials: PR
authors.lastname: Johnson
authors.forename: J L
authors.initials: JL
authors.lastname: Gaylor
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis*; D006224:Cricetinae; D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007810:Lanosterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011973:Receptors, LDL / Q000378:metabolism; D058886:Sterol 14-Demethylase; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; D007810:Lanosterol; C015316:lanostenol; D002784:Cholesterol; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase