Japan Tobacco Inc, Central Pharmaceutical Research Institute, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan,
J Pharmacol Exp Ther. 2011 Feb;336(2):321-7. doi: 10.1124/jpet.110.173807. Epub 2010 Oct 25.
Inhibitors of microsomal triglyceride transfer protein (MTP) expressed in the liver and small intestine are potential candidates for lipid-lowering agents. However, inhibition of hepatic MTP could lead to significant safety issues such as fatty liver disease. To develop a specific inhibitor of intestinal MTP, JTT-130 [diethyl-2-({3-dimethylcarbamoyl-4-[(4'-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}acetyloxymethyl)-2-phenylmalonate], was designed to be rapidly hydrolyzed in the absorption process. Here, we describe JTT-130, an intestine-specific MTP inhibitor, and evaluate its pharmacological properties. In in vitro metabolic stability tests, JTT-130 was readily hydrolyzed during incubation with liver S9 from humans, hamsters, and rats. In an in vitro triglyceride (TG) transfer assay with human intestinal MTP, JTT-130 potently inhibited TG transfer activity with an IC(50) value of 0.83 nM. When orally administered to hamsters, JTT-130 significantly suppressed an increase in chylomicron-TG after olive oil loading at 0.3 mg/kg and above but did not inhibit TG secretion from the liver at doses of up to 1000 mg/kg, indicating an inhibitory action highly specific for the small intestine. In rats orally administered [(14)C]triolein, JTT-130 potently suppressed an increase in blood (14)C radioactivity and increased (14)C radioactivity in the upper small intestine and the intestinal lumen. In hyperlipidemic hamsters fed a high-fat and high-cholesterol diet, repeated dosing with JTT-130 for 2 weeks reduced TG and cholesterol levels in the plasma and TG content in the liver. These results indicated that JTT-130 is a potent inhibitor specific to intestinal MTP and suggested that JTT-130 would be a useful compound for the treatment of dyslipidemia without inducing hepatotoxicity.
微粒体甘油三酯转移蛋白（MTP）抑制剂在肝脏和小肠中表达，是潜在的降脂药物候选物。然而，抑制肝 MTP 可能导致显著的安全问题，如脂肪肝疾病。为了开发一种特异性的肠 MTP 抑制剂，设计了 JTT-130[二乙基-2-({3-二甲基氨基甲酰基-4-[(4'-三氟甲基联苯-2-羰基)氨基]苯基}乙酰氧甲基)-2-苯基丙二酸酯]，使其在吸收过程中迅速水解。本文描述了 JTT-130，一种肠特异性 MTP 抑制剂，并评价了其药理学性质。在体外代谢稳定性试验中，JTT-130 在与来自人、仓鼠和大鼠的肝 S9 孵育时容易水解。在人肠 MTP 的体外甘油三酯（TG）转移试验中，JTT-130 对 TG 转移活性具有很强的抑制作用，IC50 值为 0.83 nM。当以 0.3 mg/kg 及以上剂量口服给予仓鼠时，JTT-130 显著抑制橄榄油负荷后乳糜微粒-TG 的增加，但在高达 1000 mg/kg 的剂量下不抑制肝 TG 的分泌，表明对小肠具有高度特异性的抑制作用。在给予大鼠口服[(14)C]三油酸甘油酯的试验中，JTT-130 强烈抑制血液（14)C 放射性的增加，并增加小肠上部和肠腔中的（14)C 放射性。在给予高脂肪和高胆固醇饮食的高脂血症仓鼠中，重复给予 JTT-130 2 周可降低血浆中的 TG 和胆固醇水平以及肝中的 TG 含量。这些结果表明，JTT-130 是一种特异性抑制肠 MTP 的有效抑制剂，提示 JTT-130 将成为一种有用的化合物，可用于治疗血脂异常而不引起肝毒性。
