Yasuhara M, Saito K, Kubota H, Ohmizu H, Suzuki T
Lead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., Saitama, Japan.
Biol Pharm Bull. 1997 Oct;20(10):1056-60. doi: 10.1248/bpb.20.1056.
We investigated the effects of T-2591, a new ureidophenol derivative, on low density lipoprotein (LDL) oxidation, acyl CoA: cholesterol acyltransferase (ACAT) and foam cell formation of macrophages in vitro. T-2591 inhibited both copper ion--and endothelial cell--induced LDL oxidation with higher potencies than probucol did. It inhibited ACAT from rabbit intestine, liver and aorta, the respective IC50 values being 0.26, 4.6 and 4.1 microM. It also inhibited ACAT from the mouse macrophage cell line J774 A.1, and its IC50 value (0.067 microM) was much lower than that of CI-976 (4.1 microM). This probably accounts for the inhibition of foam cell formation measured as cholesteryl ester formation in both mouse peritoneal macrophages and J774 A.1 cells at low concentrations (IC50; 0.06 and 0.44 microM, respectively). These observations suggest that T-2591 should be evaluated as a potential tool to retard atherosclerosis in animal models.
我们研究了新型脲基酚衍生物T-2591对体外低密度脂蛋白（LDL）氧化、酰基辅酶A：胆固醇酰基转移酶（ACAT）以及巨噬细胞泡沫细胞形成的影响。T-2591抑制铜离子和内皮细胞诱导的LDL氧化，其效力高于普罗布考。它抑制兔肠道、肝脏和主动脉中的ACAT，各自的IC50值分别为0.26、4.6和4.1微摩尔。它还抑制小鼠巨噬细胞系J774 A.1中的ACAT，其IC50值（0.067微摩尔）远低于CI-976（4.1微摩尔）。这可能解释了在低浓度下（IC50分别为0.06和0.44微摩尔），T-2591对小鼠腹腔巨噬细胞和J774 A.1细胞中以胆固醇酯形成来衡量的泡沫细胞形成的抑制作用。这些观察结果表明，T-2591应作为一种潜在工具在动物模型中评估其延缓动脉粥样硬化的作用。
