Relationships between Lipophilicity and Biological Activities in a Series of Indoline-based Anti-oxidative Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors
Relationships between Lipophilicity and Biological Activities in a Series of Indoline-based Anti-oxidative Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitors
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一系列基于二氢吲哚的抗氧化酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂的亲脂性与生物活性之间的关系
DOI：
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
H. Shirahase
中科院分区：
文献类型：
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作者：
Kenji Takahashi;K. Kunishiro;M. Kasai;Tomohiro Miike;K. Kurahashi;H. Shirahase
摘要已报道了一系列新型的基于1-烷基-7-氨基-吲哚的抗氧化酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂，预计可通过抑制肠道和肝脏ACAT来降低血浆胆固醇水平，并通过抑制低密度脂蛋白（LDL）氧化来抑制巨噬细胞中的胆固醇积聚。在本研究中，亲脂性和生物活性之间的关系进行了检查，在13个衍生物。亲脂性（logP）增加，水溶性降低与1-烷基链中的碳数的依赖。对体外肠ACAT和LDL氧化的抑制活性与logP呈正相关;然而，最佳logP，在该水平的活动是最大的，这两种效果之间的差异。对体外血浆氧化的抑制活性弱依赖于logP。以10 mg/kg口服给药后衍生物的血浆浓度与logP呈负相关，与水溶性呈正相关。在喂食高胆固醇饲料的大鼠中的降胆固醇活性，以及ACAT抑制的Cmax和IC 50值的比值（有效血浆浓度的指数）与logP高度正相关，而在大鼠中对血浆氧化的离体抑制活性，以及抑制血浆氧化的Cmax和IC 50值的比值与logP呈负相关。总之，体外ACAT抑制和抗氧化活性不同地依赖于logP，并且肠吸收与基于吲哚啉的抗氧化ACAT抑制剂的亲脂性成反比。降胆固醇作用与亲脂性呈正相关，离体抗氧化作用与亲脂性呈负相关。在本系列衍生物中，最佳logP作为针对体内ACAT和脂质过氧化的生物可利用的双重抑制剂估计为3.8（1-戊基和1-异戊基衍生物）。
Abstract A novel series of 1-alkyl-7-amido-indo-line-based anti-oxidative acyl-CoA: cholesterol acyltransferase (ACAT) inhibitors have been reported and are expected to lower plasma cholesterol levels due to the inhibition of intestinal and hepatic ACAT, and to inhibit cholesterol accumulation in macrophages due to the inhibition of low density lipoprotein (LDL) oxidation. In the present study, relationships between lipophilicity and biological activities were examined in 13 derivatives. Lipophilicity (logP) increased and water solubility decreased with dependence on the number of carbons in the 1-alkyl chain. Inhibitory activity against both in vitro intestinal ACAT and LDL oxidation positively correlated with logP; however, the optimum logP, at which the level of activity is maximal, differed between these two effects. Inhibitory activity against in vitro plasma oxidation was weakly dependent on logP. Plasma concentrations of the derivatives after oral administration at 10 mg/kg correlated negatively with logP and positively with water solubility. Hypocholesterolemic activity in rats fed a high-cholesterol diet, and the ratio of Cmax and IC50 values for ACAT inhibition, an index of effective plasma concentration, positively and highly correlated with logP, while ex vivo inhibitory activity against plasma oxidation in rats, and the ratio of Cmax and IC50 values for the inhibition of plasma oxidation negatively correlated with logP. In conclusion, in vitro ACAT inhibitory and anti-oxidative activity were differently dependent on logP, and intestinal absorption was inversely dependent on lipophilicity in indoline-based anti-oxidative ACAT inhibitors. The hypocholesterolemic effect positively correlated and the ex vivo anti-oxidative effect negatively correlated with lipophilicity. Optimum logP as a bioavailable dual inhibitor against in vivo ACAT and lipid peroxidation was estimated to be 3.8 (1-pentyl and 1-isopentyl derivatives) in the present series of derivatives.
影响因子：
6.5
作者：
F. Field;S. Mathur
通讯作者：
F. Field;S. Mathur