Wetterau J R, Gregg R E, Harrity T W, Arbeeny C, Cap M, Connolly F, Chu C H, George R J, Gordon D A, Jamil H, Jolibois K G, Kunselman L K, Lan S J, Maccagnan T J, Ricci B, Yan M, Young D, Chen Y, Fryszman O M, Logan J V, Musial C L, Poss M A, Robl J A, Simpkins L M, Slusarchyk W A, Sulsky R, Taunk P, Magnin D R, Tino J A, Lawrence R M, Dickson J K, Biller S A
Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
Science. 1998 Oct 23;282(5389):751-4. doi: 10.1126/science.282.5389.751.
Patients with abetalipoproteinemia, a disease caused by defects in the microsomal triglyceride transfer protein (MTP), do not produce apolipoprotein B-containing lipoproteins. It was hypothesized that small molecule inhibitors of MTP would prevent the assembly and secretion of these atherogenic lipoproteins. To test this hypothesis, two compounds identified in a high-throughput screen for MTP inhibitors were used to direct the synthesis of a highly potent MTP inhibitor. This molecule (compound 9) inhibited the production of lipoprotein particles in rodent models and normalized plasma lipoprotein levels in Watanabe-heritable hyperlipidemic (WHHL) rabbits, which are a model for human homozygous familial hypercholesterolemia. These results suggest that compound 9, or derivatives thereof, has potential applications for the therapeutic lowering of atherogenic lipoprotein levels in humans.
无β脂蛋白血症患者，一种由微粒体甘油三酯转移蛋白（MTP）缺陷引起的疾病，不会产生含载脂蛋白B的脂蛋白。据推测，MTP的小分子抑制剂将阻止这些致动脉粥样硬化脂蛋白的组装和分泌。为了验证这一假设，在高通量筛选MTP抑制剂过程中鉴定出的两种化合物被用于指导合成一种高效的MTP抑制剂。这种分子（化合物9）在啮齿动物模型中抑制了脂蛋白颗粒的产生，并使渡边遗传性高脂血症（WHHL）兔（一种人类纯合子家族性高胆固醇血症模型）的血浆脂蛋白水平恢复正常。这些结果表明，化合物9或其衍生物在治疗性降低人类致动脉粥样硬化脂蛋白水平方面具有潜在应用。
