Frye L L, Leonard D A
Crit Rev Biochem Mol Biol. 1999;34(2):123-40. doi: 10.1080/10409239991209246.
Drugs which suppress hepatic cholesterol biosynthesis are important therapeutic tools for lowering serum cholesterol, a major risk factor in coronary heart disease. With the goal of developing molecules that will effectively shut down cholesterol biosynthesis in hepatic tissue but allow for the buildup of the isoprenes needed for the biosynthesis of polyisoprenes other than sterols, we have designed and evaluated a series of lanosterol analogs to act as dual-action inhibitors of cholesterol biosynthesis. These sterols were predicted to act as competitive inhibitors of lanosterol 14alpha-methyl demethylase (P-450DM) and as partial suppressors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), the rate-limiting enzyme in the pathway. Compounds which have been identified as dual-action inhibitors of cholesterol biosynthesis include analogs of the intermediates generated during the removal of the 14alpha-methyl group of lanosterol by P-450DM, aminolanosterols with the amine nitrogen placed in the vicinity of C-32, and lanosterol analogs with a ketone or oxime functionality at C-15. While some dual-action inhibitors require an active P-450DM for suppression of HMGR activity, others do not. The inability of some compounds to suppress HMGR activity in cells which lack P-450DM activity suggests either that these compounds require P-450DM for conversion to an active metabolite which then suppresses HMGR activity, or that they cause the accumulation of the natural demethylation intermediates resulting in the suppression of HMGR activity. Lanosterol analogs, in contrast to 25-hydroxycholesterol, do not inhibit transcription of the HMGR gene. Rather, they inhibit translation of the HMGR mRNA, and in most cases also accelerate the degradation of enzyme protein. The potential pharmacological utility of cholesterol biosynthesis inhibitors may be determined at least in part by their effects on LDL receptor (LDLR) activity. The transcriptional regulator 25-hydroxycholesterol suppresses both HMGR and LDLR activities, while the post-transcriptional regulatory lanosterol analogs exhibit a more desirable profile, lowering HMGR levels without suppressing LDLR expression, and in some cases actually enhancing cellular LDL metabolism. Lanosterol analogs which function as dual-action inhibitors of cholesterol biosynthesis promise to be useful not only as tools for dissecting the cellular regulation of cholesterol metabolism, but also as models for the development of safe, effective hypocholesterolemic agents.
抑制肝脏胆固醇生物合成的药物是降低血清胆固醇的重要治疗工具，血清胆固醇是冠心病的主要危险因素。为了开发能够有效阻断肝脏组织中胆固醇生物合成，但又能允许积累除固醇类以外的聚异戊二烯生物合成所需异戊二烯的分子，我们设计并评估了一系列羊毛甾醇类似物，使其作为胆固醇生物合成的双效抑制剂。预计这些固醇类物质可作为羊毛甾醇14α-甲基脱甲基酶（P-450DM）的竞争性抑制剂，并作为3-羟基-3-甲基戊二酰辅酶A还原酶（HMGR）的部分抑制剂，HMGR是该途径中的限速酶。已被鉴定为胆固醇生物合成双效抑制剂的化合物包括P-450DM去除羊毛甾醇14α-甲基过程中产生的中间体类似物、胺氮位于C-32附近的氨基羊毛甾醇，以及在C-15处具有酮或肟官能团的羊毛甾醇类似物。虽然一些双效抑制剂需要活性P-450DM来抑制HMGR活性，但其他抑制剂则不需要。某些化合物在缺乏P-450DM活性的细胞中无法抑制HMGR活性，这表明这些化合物要么需要P-450DM将其转化为活性代谢物，进而抑制HMGR活性，要么它们导致天然脱甲基中间体积累，从而抑制HMGR活性。与25-羟基胆固醇不同，羊毛甾醇类似物不抑制HMGR基因的转录。相反，它们抑制HMGR mRNA的翻译，并且在大多数情况下还加速酶蛋白的降解。胆固醇生物合成抑制剂的潜在药理效用可能至少部分取决于它们对低密度脂蛋白受体（LDLR）活性的影响。转录调节因子25-羟基胆固醇同时抑制HMGR和LDLR活性，而后转录调节的羊毛甾醇类似物表现出更理想的情况，降低HMGR水平而不抑制LDLR表达，并且在某些情况下实际上增强细胞内LDL代谢。作为胆固醇生物合成双效抑制剂发挥作用的羊毛甾醇类似物有望不仅作为剖析胆固醇代谢细胞调节的工具，而且作为开发安全、有效的降胆固醇药物的模型。
