Ishihara Tsukasa, Kakuta Hirotoshi, Moritani Hiroshi, Ugawa Tohru, Sakamoto Shuichi, Tsukamoto Shin ichi, Yanagisawa Isao
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, 305-8585, Ibaraki, Japan.
Bioorg Med Chem. 2003 Aug 15;11(17):3735-45. doi: 10.1016/s0968-0896(03)00336-5.
Squalene synthase (E.C. 2.5.1.21) is a microsomal enzyme which catalyzes the reductive dimerization of two molecules of farnesyl diphosphate to form squalene, and is involved in the first committed step in cholesterol biosynthesis. It is an attractive target for hypocholesterolemic and hypotriglyceridemic strategies. We synthesized a series of 3-ethylidenequinuclidine derivatives, and evaluated their ability to inhibit squalene synthase in vitro and to lower non-HDL cholesterol levels in hamsters. 3-Ethylidenequinuclidine derivatives incorporating an unsubstituted 9H-carbazole moiety reduced plasma non-HDL cholesterol levels and did not affect plasma transaminase levels, indicating a lack of hepatotoxicity. Among the novel compounds, (Z)-2-[2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 8 (YM-53579) and (E)-2-[2-fluoro-2-(quinuclidin-3-ylidene)ethoxy]-9H-carbazole hydrochloride 28 (YM-53601) were potent inhibitors of squalene synthase derived from human hepatoma cells, with IC(50) values of 160 and 79 nM, respectively. They also reduced plasma non-HDL cholesterol levels in hamsters by approximately 50 and 70%, respectively, at an oral dose of 50 mg/kg/day for 5 days.
角鲨烯合酶（E.C. 2.5.1.21）是一种微粒体酶，它催化两分子法呢基二磷酸的还原二聚反应以形成角鲨烯，并参与胆固醇生物合成的首个关键步骤。它是降胆固醇和降甘油三酯策略的一个有吸引力的靶点。我们合成了一系列3-亚乙基奎宁环衍生物，并评估了它们在体外抑制角鲨烯合酶的能力以及降低仓鼠非高密度脂蛋白胆固醇水平的能力。含有未取代的9H-咔唑部分的3-亚乙基奎宁环衍生物降低了血浆非高密度脂蛋白胆固醇水平，且不影响血浆转氨酶水平，表明没有肝毒性。在这些新化合物中，（Z）-2-[2-（奎宁环-3-亚基）乙氧基]-9H-咔唑盐酸盐8（YM-53579）和（E）-2-[2-氟-2-（奎宁环-3-亚基）乙氧基]-9H-咔唑盐酸盐28（YM-53601）是源自人肝癌细胞的角鲨烯合酶的强效抑制剂，IC（50）值分别为160和79 nM。它们在以50 mg/kg/天的口服剂量给药5天时，还分别使仓鼠血浆非高密度脂蛋白胆固醇水平降低了约50%和70%。
