SUBSTRATE-BASED INHIBITORS OF LANOSTEROL 14-ALPHA-METHYL DEMETHYLASE .1. ASSESSMENT OF INHIBITOR STRUCTURE-ACTIVITY RELATIONSHIP AND CHOLESTEROL-BIOSYNTHESIS INHIBITION PROPERTIES
SUBSTRATE-BASED INHIBITORS OF LANOSTEROL 14-ALPHA-METHYL DEMETHYLASE .1. ASSESSMENT OF INHIBITOR STRUCTURE-ACTIVITY RELATIONSHIP AND CHOLESTEROL-BIOSYNTHESIS INHIBITION PROPERTIES
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DOI：
10.1021/bi00030a003
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发表时间：
1995-08-01
期刊：
影响因子：
2.9
通讯作者：
GAYLOR, JL
中科院分区：
文献类型：
--
作者：
TRZASKOS, JM;KO, SS;GAYLOR, JL
本发明描述了一系列15-、32-和15，32-取代的羊毛甾-8-烯-3 β-醇，其用作胆固醇生物合成的抑制剂。这些试剂抑制培养细胞中羊毛甾醇14 α-甲基脱甲基酶活性以及抑制HMG-CoA还原活性。这些药物中有几种是非常有效的脱甲基酶抑制剂和还原酶抑制剂，而其他药物的活性更具选择性。选择的区域双键异构体显示出对脱甲基酶抑制的偏好，顺序如下：δ（8）> δ（7）> δ（6）=不饱和甾醇。比较还表明，4，4-二甲基甾醇总是更有效的脱甲基酶抑制剂和还原酶抑制剂比他们的4，4-bisnormethyl对应物。然而，一个广泛的胆甾醇系列的评价导致我们得出结论，脱甲基酶抑制和还原酶抑制是不平行的同一分子。此外，胆固醇，而不是氧化胆固醇，能够破坏从LDL受体的HMG-CoA还原酶的协调调节。因此，在抑制还原酶活性的水平下的胆甾醇处理增强LDL受体活性。这些结果表明，可以制备这样的化合物，其（1）是选择性还原酶抑制剂，能够剖析这些化合物的双重抑制剂性质，和（2）最大化还原酶抑制和LDL受体诱导，而没有脱甲基酶抑制，这可能导致用于降低血清胆固醇的新药剂。
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-bisnormethyl 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.