Eisele B, Budzinski R, Müller P, Maier R, Mark M
Department of Biology, Boehringer Ingelheim Research, Biberach, Germany.
J Lipid Res. 1997 Mar;38(3):564-75.
BIBB 515 (1-(4-chlorobenzoyl)-4-((4-(2-oxazolin-2-yl) benzylidene))piperidine) is a potent and selective inhibitor of 2,3-oxidosqualene cyclase (OSC) [EC 5.4.99.7]. In rats and mice BIBB 515 inhibited OSC in vivo in a dose-dependent manner after 1, 3, and 5 h with ED50 values from 0.2 to 0.5 mg/kg (1 to 5 h) in rats and 0.36 (1 h) to 15.5 (3 h) and 33.3 (5 h) mg/kg in mice. Inhibition of [14C]acetate incorporation into sterols was found to parallel the effects on OSC when measured after 1 h (mice) or 3 h (rats). ED50 calculated were 0.9 mg/kg (mice) and 0.1 mg/kg (rats). Dose-dependent lipid-lowering activity was seen in normolipemic hamsters after 11 days treatment (-19% for total cholesterol and -32% for VLDL + LDL cholesterol at 55 mg/kg BIBB 515 per day) and in hyperlipemic hamsters after 25 days (-25% for total cholesterol and -59% for LDL-cholesterol at 148 mg/kg BIBB 515 per day). Calculation of kinetic parameters revealed no relevant differences between control and treatment groups in LDL clearance or fractional catabolic rates, but significant reductions of LDL production rates (-30% to -54%). Liver LDL receptor mRNA of the treated animals was not or only slightly increased. Liver VLDL secretion as measured by the Triton WR1339 method was reduced after BIBB 515 in rats and hamsters. It is concluded that the lipid-lowering effect of BIBB 515 is mainly the result of an inhibition of LDL production rather than due to an increase in LDL catabolism. OSC inhibitors may offer a novel approach for lipid-lowering therapy.
BIBB 515（1-（4-氯苯甲酰基）-4-（（4-（2-恶唑啉-2-基）亚苄基）哌啶）是一种高效且具有选择性的2,3-氧化角鲨烯环化酶（OSC）[EC 5.4.99.7]抑制剂。在大鼠和小鼠中，BIBB 515在1、3和5小时后以剂量依赖性方式在体内抑制OSC，大鼠的ED50值为0.2至0.5毫克/千克（1至5小时），小鼠的ED50值为0.36（1小时）至15.5（3小时）和33.3（5小时）毫克/千克。当在1小时（小鼠）或3小时（大鼠）后测量时，发现[14C]乙酸掺入固醇的抑制作用与对OSC的作用平行。计算得出的ED50分别为0.9毫克/千克（小鼠）和0.1毫克/千克（大鼠）。在正常血脂的仓鼠中，经过11天的治疗后可见剂量依赖性的降脂活性（每天55毫克/千克BIBB 515时，总胆固醇降低19%，极低密度脂蛋白 + 低密度脂蛋白胆固醇降低32%），在高脂血症仓鼠中，经过25天的治疗后（每天148毫克/千克BIBB 515时，总胆固醇降低25%，低密度脂蛋白胆固醇降低59%）。动力学参数的计算显示，对照组和治疗组在低密度脂蛋白清除率或分解代谢率分数方面没有相关差异，但低密度脂蛋白生成率显著降低（-30%至-54%）。治疗动物的肝脏低密度脂蛋白受体mRNA没有增加或仅略有增加。用Triton WR1339方法测量，大鼠和仓鼠在给予BIBB 515后肝脏极低密度脂蛋白分泌减少。得出结论，BIBB 515的降脂作用主要是抑制低密度脂蛋白生成的结果，而非由于低密度脂蛋白分解代谢增加。OSC抑制剂可能为降脂治疗提供一种新方法。
