Krause B R, Black A, Bousley R, Essenburg A, Cornicelli J, Holmes A, Homan R, Kieft K, Sekerke C, Shaw-Hes M K
Department of Pharmacology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan.
J Pharmacol Exp Ther. 1993 Nov;267(2):734-43.
The in vitro potencies and hypocholesterolemic properties of CL 277,082 and PD 132301-2, two urea inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT) were compared. PD 132301-2 was several-fold more potent at inhibiting ACAT in microsomes from rat and rabbit tissues and in cultured cells (murine macrophages and the human HepG2 cell line). This disubstituted urea was also relatively specific for ACAT as other cholesterol esterifying enzymes (e.g., lecithin:cholesterol acyltransferase, pancreatic cholesterol ester hydrolase), as well as intestinal diglyceride synthesis (acyl-CoA:monoglyceride acyltransferase), were unaffected in vitro at relevant concentrations. In normal chow-fed rats, both compounds reduced plasma triglycerides at doses > 50 mg/kg, but only PD 132301-2 reduced plasma cholesterol. In rat and rabbit models of hypercholesterolemia the greater in vitro potency of PD 132301-2 translated into greater in vivo efficacy (i.e., ED50 values 2- to 3-fold higher for CL 277,082 in both acute and chronic rate models). Of particular note was the greater elevation of high-density lipoprotein-cholesterol and parenteral activity of PD 132301-2 compared to CL 277,082 in the chronic rat model. Inhibition of cholesterol absorption in rats was also greater with PD 132301-2. In guinea pigs, in which 77% of plasma cholesterol was transported in low-density lipoprotein, PD 132301-2 potently reduced plasma total cholesterol (lowest significant dose = 1 mg/kg) as well as plasma triglycerides. CL 277,082 only reduced cholesterol at doses > 100 mg/kg in this low-density lipoprotein model. In a canine model of hypercholesterolemia CL 277,082 was inactive at doses up to 50 mg/kg, but PD 132301-2 was active at 3 mg/kg. Moreover, efficacy in dogs with PD 132301-2 was positively correlated with plasma drug concentration, an observation not previously demonstrated for other hypolipidemic drugs. The combined data illustrate that pharmacologic activities can vary widely among ACAT inhibitors of the same general class. In addition, the unique observation of proportionality between efficacy and blood drug levels in nonrodent animal models may not only help to simplify early stages in drug development but also may help to predict or monitor a direct action of the drug on vascular disease.
比较了两种酰基辅酶A：胆固醇酰基转移酶（ACAT）尿素抑制剂CL 277,082和PD 132301-2的体外效力和降胆固醇特性。PD 132301-2在抑制大鼠和兔组织微粒体以及培养细胞（小鼠巨噬细胞和人HepG2细胞系）中的ACAT方面效力高几倍。这种二取代尿素对ACAT也具有相对特异性，因为其他胆固醇酯化酶（如卵磷脂：胆固醇酰基转移酶、胰腺胆固醇酯水解酶）以及肠道甘油二酯合成（酰基辅酶A：甘油单酯酰基转移酶）在相关浓度下体外不受影响。在正常饲料喂养的大鼠中，两种化合物在剂量>50 mg/kg时均降低血浆甘油三酯，但只有PD 132301-2降低血浆胆固醇。在高胆固醇血症的大鼠和兔模型中，PD 132301-2更高的体外效力转化为更高的体内疗效（即在急性和慢性大鼠模型中，CL 277,082的ED50值高2至3倍）。特别值得注意的是，在慢性大鼠模型中，与CL 277,082相比，PD 132301-2使高密度脂蛋白胆固醇升高幅度更大且具有肠外活性。PD 132301-2对大鼠胆固醇吸收的抑制作用也更强。在豚鼠中，其血浆胆固醇的77%由低密度脂蛋白转运，PD 132301-2能有效降低血浆总胆固醇（最低有效剂量=1 mg/kg）以及血浆甘油三酯。在这个低密度脂蛋白模型中，CL 277,082仅在剂量>100 mg/kg时降低胆固醇。在高胆固醇血症犬模型中，CL 277,082在剂量高达50 mg/kg时无活性，但PD 132301-2在3 mg/kg时具有活性。此外，PD 132301-2在犬中的疗效与血浆药物浓度呈正相关，这一观察结果此前在其他降血脂药物中未得到证实。综合数据表明，同一类ACAT抑制剂的药理活性可能有很大差异。此外，在非啮齿动物模型中观察到的疗效与血药水平之间的独特比例关系不仅可能有助于简化药物开发的早期阶段，还可能有助于预测或监测药物对血管疾病的直接作用。
