Department of Pharmaceutical Chemistry, School of Pharmacy, University of Athens, 15771 Athens, Greece.
Curr Med Chem. 2011;18(29):4418-39. doi: 10.2174/092986711797287557.
Atherosclerosis and related heart disease is strongly associated with elevated blood levels of total (and LDL) cholesterol. Due to the widespread incidence as well as severity of this pathological condition, major efforts have been made for the discovery and development of hypocholesteroleamic agents. In the past few decades, HMG-CoA reductase inhibitors (statins) are being extensively used as lipid lowering drugs. These agents act predominantly by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) that is the rate limiting step of cholesterol biosynthesis. Both the success as well as drawbacks of HMGRIs, have led to the investigation and design of inhibitors of other (downstream) enzymes involved in the multistep cholesterol biosynthetic pathway. One such class of agents consists of the squalene sythase inhibitors which act at the first and solely committed step towards the biosynthesis of the cholesterol nucleus. This target is considered not to interfere with the biosynthesis of other biologically important molecules and thus a better side-effect profile is expected for these inhibitors. Several classes of squalene synthase inhibitors (SQSIs), such as substrate or transition-state analogues, zaragozic acids or 2,8- dioxabicyclo[3.2.1]octane derivatives, dicarboxylic acid and quinuclidine derivatives, 4,1-benzoxazepine as well as substituted morpholine derivatives, have been studied as potent inhibitors of squalene synthase. So far only one benzoxazepine derivative (TAK-475) has been evaluated in advanced clinical trials. In this article we review the up to date research and literature on the therapeutic potential of this relatively new class of compounds, the drug discovery efforts towards the development of active squalene synthase inhibitors, their activity profile and effectiveness, as well as their structure-activity relationships.
动脉粥样硬化和相关的心脏病与血液中总胆固醇（和 LDL 胆固醇）水平升高密切相关。由于这种病理状况的广泛发生和严重程度，人们已经做出了巨大的努力来发现和开发降胆固醇药物。在过去的几十年中，HMG-CoA 还原酶抑制剂（他汀类药物）被广泛用作降脂药物。这些药物主要通过抑制酶 3-羟基-3-甲基戊二酰辅酶 A 还原酶（HMGR）来发挥作用，HMGR 是胆固醇生物合成的限速步骤。HMGRIs 的成功和缺点都导致了对涉及多步胆固醇生物合成途径的其他（下游）酶抑制剂的研究和设计。其中一类药物是鲨烯合酶抑制剂，它们作用于胆固醇核生物合成的第一步和唯一的关键步骤。这个靶点被认为不会干扰其他生物重要分子的生物合成，因此预计这些抑制剂的副作用较小。几种鲨烯合酶抑制剂（SQSIs）类别，如底物或过渡态类似物、扎拉格酸或 2,8-二氧杂环辛烷衍生物、二羧酸和奎宁环衍生物、4,1-苯并恶嗪以及取代吗啉衍生物，已被研究作为鲨烯合酶的有效抑制剂。到目前为止，只有一种苯并恶嗪衍生物（TAK-475）在临床试验中进行了评估。本文综述了这类相对较新的化合物的治疗潜力的最新研究和文献，开发活性鲨烯合酶抑制剂的药物发现努力，它们的活性概况和有效性，以及它们的结构-活性关系。
