Squalene synthase is one of the most promising pharmaceutical targets to treat hyperlipidemia. Inhibition of the squalene synthase causes a decrease in the hepatic cholesterol concentration. We have already reported the design and synthesis of highly potent benzhydrol-type squalene inhibitors. Although these templates showed unique and potent cyclic active conformations via intramolecular hydrogen bonds, the in vivo cholesterol-lowering efficacy was insufficient. We attempted to improve their potential as an orally active medicine. In our medicinal chemistry effort, cyclized 11-membered ring templates were acquired. The novel series of compounds exhibited potent squalene synthase inhibitory activity, and one of the derivatives, isomer A-(1S, 3R)-14i, showed plasma lipid-lowering efficacy in hamster and marmoset repeated-dose studies. Our findings provide valuable insights into the design and development of novel and unique 11-membered ring-type highly potent squalene synthase inhibitors.

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作为角鲨烯合酶抑制剂的新型 11 元模板的发现

角鲨烯合酶是治疗高脂血症最有前途的药物靶点之一。角鲨烯合酶的抑制导致肝脏胆固醇浓度降低。我们已经报道了高效二苯甲基型角鲨烯抑制剂的设计和合成。尽管这些模板通过分子内氢键显示出独特且有效的环状活性构象，但体内降胆固醇功效不足。我们试图提高它们作为口服活性药物的潜力。在我们的药物化学工作中，获得了环化 11 元环模板。该系列新型化合物表现出有效的角鲨烯合酶抑制活性，其中一种衍生物异构体 A -( 1 S , 3 R )- 14i在仓鼠和狨猴重复剂量研究中显示出降低血浆脂质的功效。我们的研究结果为新型独特的 11 元环型高效角鲨烯合酶抑制剂的设计和开发提供了宝贵的见解。