Trivedi B K, Purchase T S, Holmes A, Augelli-Szafran C E, Essenburg A D, Hamelehle K L, Stanfield R L, Bousley R F, Krause B R
Department of Medicinal Chemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105.
J Med Chem. 1994 May 27;37(11):1652-9. doi: 10.1021/jm00037a016.
We recently described our initial structure-activity relationship (SAR) studies on a series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). From this series of analogs, compound 1 (PD 129337) was identified as a potent inhibitor of ACAT with an IC50 value of 17 nM. It was also shown to dose-dependently lower plasma cholesterol in cholesterol-fed rats. However, further investigation led to the suggestion that this compound was poorly absorbed, due to a lack of efficacy when administered by gavage in an aqueous vehicle. To overcome this deficiency, we continued our SAR study on this novel series of ACAT inhibitors using an acute in vivo screen in which the compounds are administered to rats in an aqueous, CMC/Tween suspension vehicle. Modification of the N'-phenyl moiety by incorporating functional groups which were amenable to forming salts and/or polar groups to reduce lipophilicity led to the identification of several inhibitors which displayed excellent efficacy employing this protocol. Overall, substitution on the phenyl ring in the ortho, meta, or para positions led to inhibitors with only a slight decrease in potency in vitro compared to the parent unsubstituted compound. Bulkier groups in the para position tended to lower the ACAT inhibitory activity in vitro. Polar groups, such as carboxyl (33,34), lowered in vitro activity significantly, suggesting that polar-ionic interactions are disfavored for the enzyme activity. From this series, compound 28 was evaluated further in secondary in vivo screens. In a chronic cholesterol-fed rat model of hypercholesterolemia, compound 28 dose-dependently reduced nonHDL cholesterol and significantly elevated HDL cholesterol. It showed significantly greater aqueous solubility than the parent compound 1. However, it was shown to cause adrenal toxicity in guinea pigs. This led us to design a series of homologs (44-51) with increased basicity and lower lipophilicity. Some of these compounds were more potent ACAT inhibitors in vitro and demonstrated excellent hypocholesterolemic activity in vivo. Interestingly, compound 45, unlike 28, did not produce adrenal toxicity in guinea pigs and demonstrated excellent lipid-modulating activity in the chronic model of preestablished dyslipidemia in rats.
我们最近描述了我们对一系列N-苯基-N'-芳烷基脲和N-苯基-N'-(1-苯基环烷基)脲作为酰基辅酶A：胆固醇酰基转移酶(ACAT)抑制剂的初步构效关系(SAR)研究。在这一系列类似物中，化合物1(PD 129337)被鉴定为ACAT的有效抑制剂，IC50值为17 nM。在喂食胆固醇的大鼠中，它还显示出剂量依赖性地降低血浆胆固醇。然而，进一步的研究表明，该化合物吸收不良，因为在水性载体中通过灌胃给药时缺乏疗效。为了克服这一缺陷，我们使用急性体内筛选继续对这一系列新型ACAT抑制剂进行SAR研究，在该筛选中，将化合物以水性、CMC/吐温悬浮液载体给予大鼠。通过引入易于形成盐和/或极性基团以降低亲脂性的官能团对N'-苯基部分进行修饰，从而鉴定出了几种采用该方案显示出优异疗效的抑制剂。总体而言，与未取代的母体化合物相比，在邻位、间位或对位的苯环上进行取代导致抑制剂的体外效力仅略有降低。对位上较大的基团往往会降低体外ACAT抑制活性。极性基团，如羧基(33,34)，会显著降低体外活性，这表明极性离子相互作用不利于酶活性。从这一系列中，化合物28在二级体内筛选中得到了进一步评估。在高胆固醇血症的慢性喂食胆固醇大鼠模型中，化合物28剂量依赖性地降低非高密度脂蛋白胆固醇并显著升高高密度脂蛋白胆固醇。它显示出比母体化合物1明显更高的水溶性。然而，它在豚鼠中显示出引起肾上腺毒性。这促使我们设计了一系列碱性增加和亲脂性降低的同系物(44-51)。其中一些化合物在体外是更有效的ACAT抑制剂，并在体内表现出优异的降胆固醇活性。有趣的是，与化合物28不同，化合物45在豚鼠中不会产生肾上腺毒性，并且在大鼠预先建立的血脂异常慢性模型中表现出优异的脂质调节活性。
