Therapeutic success of statins has distinctly established inhibition of de novo hepatic cholesterol synthesis as an effective approach to lower plasma LDL-cholesterol, the major risk factor for atherosclerosis and coronary heart disease. Statins inhibit HMG CoA reductase, a rate limiting enzyme which catalyses conversion of HMG CoA to mevalonic acid. However, in this process statins also inhibit the synthesis of several non-sterols e.g. dolichols and ubiquinone, which are implicated in side effects observed with statins. This prompted many major pharmaceutical companies in 1990s to target selective cholesterol synthesis beyond farnesyl pyrophosphate. The enzymes squalene synthetase, squalene epoxidase and oxidosqualene cyclase were identified as potential targets. Though inhibitors of these enzymes have been developed, till date no compound has been reported to have entered clinical trials. We evaluated the literature to understand merits and demerits of pursuing squalene epoxidase as a target for hypocholesterolemic drug development. Squalene epoxidase catalyses the conversion of squalene to 2,3-oxidosqualene. Although it has been extensively exploited for antifungal drug development, it has received little attention as a target for hypocholesterolemic drug design. This enzyme though recognized in the early 1970s was cloned 25 years later. This enzyme is an attractive step for pharmacotherapeutic intervention as it is the secondary rate limiting enzyme and blocking cholesterol synthesis at this step may result in accumulation of only squalene which is known to be stable and non toxic. Synthesis of several potent, orally bioavailable inhibitors of squalene epoxidase has been reported from Yamonuchi, Pierre Fabre and Banyu pharmaceuticals. Preclinical studies with these inhibitors have clearly demonstrated the potential of squalene epoxidase inhibitors as hypocholesterolemic agents. Hypochloesterolemic therapy is intended for prolonged duration and safety is an important determinant in clinical success. Lack of clinical trials, despite demonstrated preclinical efficacy by oral route, prompted us to evaluate safety concerns with squalene epoxidase inhibitors. In dogs, NB-598, a potent competitive squalene epoxidase inhibitor has been reported to exhibit signs of dermatitis like toxicity which has been attributed by some reviewers to accumulation of squalene in skin cells. Tellurium, a non-competitive inhibitor of squalene epoxidase has been associated with neuropathy in weanling rats. On the other hand, increased plasma levels of squalene in animals and humans (such as occurring subsequent to dietary olive oil or squalene administration) are safe and associated with beneficial effect such as chemoprevention and hypocholesterolemic activity. In our view, high circulating levels of squalene epoxidase inhibitor may be responsible for dermatitis and neuropathy. Competitive inhibition and pharmacokinetic profile minimizing circulating plasma levels (e.g. by hepatic sequestration and high first pass metabolism) could be important determinants in circumventing safety concerns of squalene epoxidase inhibitors. Recently, cholesterol-lowering effect of green tea has been attributed to potent squalene epoxidase inhibition, which can be consumed in much higher doses without toxicological effect. These facts strengthen optimism for developing clinically safe squalene epoxidase inhibitors. Put in perspective squalene epoxidase appears to be undervalued target which merits attention for development of better hypocholesterolemic drugs.

中文翻译：

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角鲨烯环氧酶作为降血脂药的靶标被重新研究。

他汀类药物的治疗成功已明确确立了从头进行肝胆固醇合成的抑制，这是降低血浆LDL-胆固醇的有效方法，LDL-胆固醇是动脉粥样硬化和冠心病的主要危险因素。他汀类药物抑制HMG CoA还原酶，这是一种速率限制酶，可催化HMG CoA转化为甲羟戊酸。但是，在此过程中，他汀类药物也抑制了几种非甾醇的合成，例如多醇和泛醌，这与他汀类药物的副作用有关。这促使许多大型制药公司在1990年代将靶向胆固醇的合成范围扩展到了法呢基焦磷酸之外。角鲨烯合成酶，角鲨烯环氧酶和氧化角鲨烯环化酶被确定为潜在目标。尽管已开发出这些酶的抑制剂，迄今为止，尚未有化合物被报道进入临床试验。我们评估了文献，以了解将角鲨烯环氧酶作为降胆固醇药开发目标的优缺点。角鲨烯环氧酶催化角鲨烯向2，3-氧化角鲨烯的转化。尽管它已被广泛用于抗真菌药物的开发，但作为降血脂药设计的目标却很少受到关注。这种酶虽然在1970年代初被发现，但在25年后被克隆。该酶是药物治疗干预的一个有吸引力的步骤，因为它是次要的限速酶，在此步骤中阻断胆固醇的合成可能只会导致已知稳定且无毒的角鲨烯蓄积。几种强效合成剂，Yamonuchi，Pierre Fabre和Banyu制药公司已经报道了口服生物可利用的鲨烯环氧酶抑制剂。用这些抑制剂进行的临床前研究清楚地表明了角鲨烯环氧酶抑制剂作为降胆固醇药的潜力。降血脂治疗旨在延长病程，安全性是临床成功的重要决定因素。尽管通过口服途径证明了临床前疗效，但缺乏临床试验促使我们评估鲨烯环氧酶抑制剂的安全性。据报道，在狗中，强效角鲨烯环氧酶抑制剂NB-598表现出皮肤炎的迹象，如毒性，一些评论者将其归因于角鲨烯在皮肤细胞中的积累。碲，角鲨烯环氧酶的非竞争性抑制剂与断奶大鼠的神经病变有关。另一方面，动物和人体内角鲨烯血浆水平的升高（例如在食用橄榄油或角鲨烯给药后发生）是安全的，并具有诸如化学预防和降血脂活性等有益作用。我们认为，角鲨烯环氧酶抑制剂的高循环水平可能是引起皮炎和神经病的原因。竞争性抑制作用和药代动力学特征可最大程度地降低循环血浆水平（例如，通过肝隔离和高首过代谢），这可能是规避角鲨烯环氧酶抑制剂安全性的重要决定因素。最近，绿茶降低胆固醇的作用归因于有效的角鲨烯环氧酶抑制作用，可以以更高的剂量服用而无毒理学作用。这些事实增强了开发临床上安全的角鲨烯环氧酶抑制剂的乐观性。纵观角鲨烯环氧酶似乎是被低估的目标，应引起人们对开发更好的降胆固醇药的关注。