Roark W H, Padia J, Bolton G L, Blankley C J, Essenburg A D, Stanfield R L, Bousley R F, Krause B R, Roth B D
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1995 Jan;3(1):29-39. doi: 10.1016/0968-0896(94)00144-r.
To examine the effects of bioisosteric replacement on the biological activity of our previously disclosed disubstituted urea inhibitors of the enzyme acyl-CoA:cholesterol acyltransferase (ACAT), we prepared a series of N'-substituted and N',N'-disubstituted glycine anilides. These compounds were tested for the ability to inhibit ACAT in vitro and lower plasma total cholesterol in cholesterol-fed rats given a single high-fat, high-cholesterol meal. ACAT inhibitory potency was greatest in compounds containing 2,6-diisopropyl substituents in the anilide portion with the glycine nitrogen substituted by a 1,1-diphenylmethyl moiety. Small improvements in potency in vitro were obtained by substitution of electron donating groups in the 2-, 3- or 5-positions of the aryl rings of the 1,1-diphenylmethyl moiety, but not by substitution in the 4-position. In vitro potency was maintained, but not improved by acylation of the glycine nitrogen. Through a QSAR analysis of in vitro ACAT inhibition for this set of compounds, an equation could be derived which accounted for 85% of the variance in the dataset. An optimal clogp of 6.65 was found, comparable to that found for other series of ACAT inhibitors. In general, compounds from this series displayed inhibitory potency against ACAT in vitro and hypocholesterolemic activity in the in vivo rat model of hypercholesterolemia comparable to that found with the ureas.
为了研究生物电子等排体替换对我们先前公开的酰基辅酶A：胆固醇酰基转移酶（ACAT）的二取代脲抑制剂生物活性的影响，我们制备了一系列N'-取代和N'，N'-二取代甘氨酸苯胺。测试了这些化合物在体外抑制ACAT以及在给予单次高脂、高胆固醇餐食的胆固醇喂养大鼠中降低血浆总胆固醇的能力。在苯胺部分含有2,6-二异丙基取代基且甘氨酸氮被1,1-二苯甲基部分取代的化合物中，ACAT抑制效力最大。通过在1,1-二苯甲基部分的芳环的2-、3-或5-位取代供电子基团，体外效力有小的提高，但在4-位取代则没有。甘氨酸氮的酰化维持了体外效力，但没有提高。通过对这组化合物的体外ACAT抑制进行定量构效关系（QSAR）分析，可以得出一个方程，该方程解释了数据集中85%的方差。发现最佳的 clogP 为6.65，与其他系列的ACAT抑制剂相当。一般来说，该系列化合物在体外对ACAT显示出抑制效力，在高胆固醇血症的体内大鼠模型中具有与脲类相当的降胆固醇活性。
