Takahashi Kenji, Kunishiro Kazuyoshi, Kasai Masayasu, Miike Tomohiro, Kurahashi Kazuyoshi, Shirahase Hiroaki
Research Laboratories, Kyoto Pharmaceutical Industries, Ltd., Kyoto, Japan.
Arzneimittelforschung. 2008;58(12):666-72. doi: 10.1055/s-0031-1296569.
A novel series of 1-alkyl-7-amido-indoline-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.
已报道了一系列新型的基于1-烷基-7-氨基吲哚啉的抗氧化酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂，由于其对肠道和肝脏ACAT的抑制作用，有望降低血浆胆固醇水平，并且由于对低密度脂蛋白（LDL）氧化的抑制作用，能够抑制巨噬细胞中的胆固醇积累。在本研究中，对13种衍生物的亲脂性与生物活性之间的关系进行了研究。亲脂性（logP）随着1-烷基链中碳原子数的增加而增加，水溶性则降低。对体外肠道ACAT和LDL氧化的抑制活性均与logP呈正相关；然而，这两种效应的最大活性水平对应的最佳logP不同。对体外血浆氧化的抑制活性对logP的依赖性较弱。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。在高胆固醇饮食喂养的大鼠中，降胆固醇活性以及ACAT抑制的Cmax与IC50值之比（有效血浆浓度的指标）与logP呈正相关且高度相关，而大鼠体内对血浆氧化的体外抑制活性以及血浆氧化抑制的Cmax与IC50值之比与logP呈负相关。总之，体外ACAT抑制和抗氧化活性对logP的依赖性不同，在基于吲哚啉的抗氧化ACAT抑制剂中，肠道吸收与亲脂性呈负相关。降胆固醇作用与亲脂性呈正相关，体外抗氧化作用与亲脂性呈负相关。在本系列衍生物中，作为体内ACAT和脂质过氧化的生物可利用双重抑制剂的最佳logP估计为3.8（1-戊基和1-异戊基衍生物）。
