Salisbury B G, Davis H R, Burrier R E, Burnett D A, Bowkow G, Caplen M A, Clemmons A L, Compton D S, Hoos L M, McGregor D G
Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Atherosclerosis. 1995 May;115(1):45-63. doi: 10.1016/0021-9150(94)05499-9.
The amount of cholesterol that circulates in the plasma as lipoproteins can be affected by the balance of cholesterol metabolism within and between the intestines and liver. In the present report, we describe a novel hypocholesterolemic agent and document its pharmacological effects in animal models of hypercholesterolemia. The oral administration of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH 48461) reduced plasma cholesterol concentrations in cholesterol-fed hamsters, rats and rhesus monkeys with ED50s of 1, 2 and 0.2 mg/kg per day, respectively, SCH 48461 was also highly effective in reducing hepatic cholesteryl ester accumulation in cholesterol-fed hamsters and rats after 7 days of treatment. In one 3 week study, rhesus monkeys were fed a 0.25% cholesterol/22% saturated fat diet with or without SCH 48461. At the end of the 3 week period the control group's VLDL + LDL-cholesterol increased to 180 Mg/dl from a baseline of approximately 65 mg/dl while plasma apolipoprotein B levels had doubled. Animals treated daily with 1 mg/kg SCH 48461 maintained their baseline levels of VLDL + LDL-cholesterol, HDL-cholesterol, and plasma apolipoproteins B and A-I. After 3 weeks the diets of the two groups were switched. Within 1 week SCH 48461 (1 mg/kg per day) rapidly reversed the elevated VLDL + LDL-cholesterol levels of the previous control group to near baseline values. SCH 48461 exerted its hypocholesterolemic effect through the inhibition of cholesterol absorption. A dose of 10 mg/kg per day inhibited cholesterol absorption in cholesterol-fed hamsters by 68% while a similar reduction was achieved in chow-fed monkeys with 3 mg/kg per day. This latter dose inhibited cholesterol absorption in cholesterol-fed monkeys by 95%. Treatment of cholesterol-fed monkeys with 10 mg/kg per day SCH 48461 significantly increased fecal neutral sterol excretion (52 vs. 32 mg/kg) but had no effect on acidic sterol excretion. Using a 2-h absorption model in cholesterol-fed hamsters, SCH 48461 caused a 46% inhibition of unesterified [14C]cholesterol accumulation in the intestinal wall and a 90% inhibition of cholesteryl ester formation at a dose of 10 mg/kg. Similar data were observed when the plasma radioactivity was assessed, indicating inhibition of both free (61%) and esterified (85%) cholesterol appearance. In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)
作为脂蛋白在血浆中循环的胆固醇量，会受到肠道和肝脏内部以及它们之间胆固醇代谢平衡的影响。在本报告中，我们描述了一种新型降胆固醇药物，并记录了其在高胆固醇血症动物模型中的药理作用。口服(3R,4S)-1,4-双-(4-甲氧基苯基)-3-(3-苯基丙基)-2-氮杂环丁烷酮（SCH 48461）可降低喂食胆固醇的仓鼠、大鼠和恒河猴的血浆胆固醇浓度，其半数有效剂量（ED50）分别为每天1、2和0.2毫克/千克。在治疗7天后，SCH 48461对降低喂食胆固醇的仓鼠和大鼠肝脏胆固醇酯积累也非常有效。在一项为期3周的研究中，给恒河猴喂食含0.25%胆固醇/22%饱和脂肪的饮食，其中一组添加SCH 48461，另一组不添加。在3周实验期结束时，对照组的极低密度脂蛋白（VLDL）+低密度脂蛋白（LDL）胆固醇从基线水平约65毫克/分升增加到180毫克/分升，而血浆载脂蛋白B水平增加了一倍。每天用1毫克/千克SCH 48461治疗的动物，其VLDL + LDL胆固醇、高密度脂蛋白（HDL）胆固醇以及血浆载脂蛋白B和A-I的水平维持在基线水平。3周后，两组的饮食进行了互换。在1周内，每天1毫克/千克的SCH 48461迅速将前对照组升高的VLDL + LDL胆固醇水平逆转至接近基线值。SCH 48461通过抑制胆固醇吸收发挥其降胆固醇作用。每天10毫克/千克的剂量可使喂食胆固醇的仓鼠的胆固醇吸收抑制68%，而每天3毫克/千克的类似剂量可使喂食普通食物的猴子的胆固醇吸收减少。后一剂量可使喂食胆固醇的猴子的胆固醇吸收抑制95%。每天用10毫克/千克SCH 48461治疗喂食胆固醇的猴子，可显著增加粪便中性固醇排泄（从32毫克/千克增加到52毫克/千克），但对酸性固醇排泄无影响。在喂食胆固醇的仓鼠中使用2小时吸收模型，剂量为10毫克/千克时，SCH 48461可使肠壁中未酯化的[14C]胆固醇积累抑制46%，胆固醇酯形成抑制90%。评估血浆放射性时也观察到类似数据，表明游离胆固醇（61%）和酯化胆固醇（85%）的出现均受到抑制。相比之下，强效酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂CI-976在抑制胆固醇酯化（98%抑制）的同时，不影响游离胆固醇进入肠道的摄取。（摘要截选至400字）
