We describe our molecular design of aortic-selective acyl-coenzyme A:cholesterol O-acyltransferase (ACAT, also abbreviated as SOAT) inhibitors, their structure–activity relationships (SARs) and their pharmacokinetic (PK) and pharmacological profiles. The connection of two weak ligands—N-(2,6-diisopropylphenyl)acetamide (50% inhibitory concentration [IC₅₀] = 8.6 μM) and 2-(methylthio)benzo[d]oxazole (IC₅₀ = 31 μM)—via a linker comprising a 6 methylene group chains yielded a highly potent molecule, 9-(benzo[d]oxazol-2-ylthio)-N-(2,6-diisopropylphenyl)nonanamide (3h) that exhibited high potency (IC₅₀ = 0.004 μM) toward aortic ACAT. This head-to-tail design made it possible to markedly enhance the activity to 2150- to 7750-fold and to discriminate the isoform-selectivity based on the double-induced fit mechanism. At doses of 1 and 3 mg/kg, 3h significantly decreased the lipid-accumulation areas in the aortic arch to 74 and 69%, respectively without reducing the plasma total cholesterol level in high fat- and cholesterol-fed F₁B hamsters. Here, we demonstrate the antiatherosclerotic effect of 3h in vivo via its direct action on aortic ACAT and its powerful modulator of cholesterol level. This molecule is a potential therapeutic agent for the treatment of diseases involving ACAT-1 overexpression.

我们描述了我们的主动脉选择性酰基辅酶A：胆固醇O-酰基转移酶（ACAT，也缩写为SOAT）抑制剂的分子设计，其结构-活性关系（SARs）以及它们的药代动力学（PK）和药理学特征。两个弱配体-N-（2,6-二异丙基苯基）乙酰胺（50％抑制浓度[IC ₅₀ ] = 8.6μM）和2-（甲硫基）苯并[ d ]恶唑（IC ₅₀  = 31μM）的连接包括6支亚甲基链的连接体，得到一种高度有效分子，9-（苯并[ d ]恶唑-2-基硫基） - ñ - （2,6-二异丙基）壬酰胺（3H），其表现出高效力（IC ₅₀ = 0.004μM）朝向主动脉ACAT。这种从头到尾的设计使将活性显着提高到2150至7750倍，并基于双重诱导的拟合机制来区分同工型选择性成为可能。在1 mg / kg和3 mg / kg的剂量下，3h显着降低了主动脉弓的脂质蓄积面积，分别降至74％和69％，而没有降低高脂和高胆固醇喂养的F ₁ B仓鼠的血浆总胆固醇水平。在这里，我们通过对主动脉ACAT的直接作用及其强大的胆固醇水平调节剂，证明了3h 在体内的抗动脉粥样硬化作用。该分子是用于治疗涉及ACAT-1过表达的疾病的潜在治疗剂。