Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-((fluorophenoxy)benzyl)-N'-arylureas with weak toxicological effects on adrenal glands.

Tanaka A; Terasawa T; Hagihara H; Ishibe N; Sawada M; Sakuma Y; Hashimoto M; Takasugi H; Tanaka H

首页> 外文期刊>Journal of Medicinal Chemistry >Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-((fluorophenoxy)benzyl)-N'-arylureas with weak toxicological effects on adrenal glands.

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Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-((fluorophenoxy)benzyl)-N'-arylureas with weak toxicological effects on adrenal glands.

机译：酰基辅酶A抑制剂：胆固醇O-酰基转移酶。 3.发现对肾上腺具有弱毒理学作用的一系列新的N-烷基-N-（（氟苯氧基）苄基）-N'-芳基脲。

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A series of N-alkyl-N-[(fluorophenoxy)benzyl]-N'-arylureas were prepared and evaluated for their ability to inhibit intestinal acyl-CoA:cholesterol O-acyltransferase and to inhibit accumulation of cholesteryl esters in macrophages in vitro. In vivo hypocholesterolemic activity was assessed in cholesterol-fed rats by oral administration as a dietary admixture and/or by gavage in a PEG400 vehicle. Modification of the alkyl substituent on the N'-aryl moiety and on the urea nitrogen significantly influenced macrophage assay in vitro. Toxicological study revealed a distinct relationship between macrophage assay and the toxicity observed in adrenal glands of rabbits treated with representatives of this series of compounds. Investigations utilizing the macrophage assay as an indicator for adrenal toxicity led to the identification of compounds 1g (FR190809) and 1k (FR186485, or FR195249 as its hydrochloride salt) as potent, nonadrenotoxic, orally efficacious ACAT inhibitors irrespective of the administration method.

机译：制备了一系列的N-烷基-N-[（氟苯氧基）苄基] -N'-芳基脲，并评价了它们在体外抑制肠酰基-CoA：胆固醇O-酰基转移酶和抑制胆固醇酯在巨噬细胞中积累的能力。在胆固醇喂养的大鼠中，通过饮食混合物和/或通过在PEG400载体中强饲来评估其体内的降胆固醇活性。 N'-芳基部分和尿素氮上的烷基取代基的修饰在体外显着影响巨噬细胞测定。毒理学研究表明巨噬细胞测定与用该系列化合物代表治疗的兔肾上腺中观察到的毒性之间存在明显的关系。利用巨噬细胞测定作为肾上腺毒性指标的研究导致鉴定化合物1g（FR190809）和1k（FR186485或FR195249作为其盐酸盐）是有效，无肾上腺素，口服有效的ACAT抑制剂，而与给药方法无关。

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来源
《Journal of Medicinal Chemistry》 |1998年第22期|共13页
作者
Tanaka A; Terasawa T; Hagihara H; Ishibe N; Sawada M; Sakuma Y; Hashimoto M; Takasugi H; Tanaka H;
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正文语种 eng
中图分类药学;
关键词
Anticholesteremic Agents; Enzyme Inhibitors; Pyridines; Sterol O Acyltransferase antagonists and inhibitors; 抗胆固醇血症药; 酶抑制剂; 吡啶类; 尿素;

机译：Anticholesteremic Agents;Enzyme Inhibitors;Pyridines;Sterol O Acyltransferase antagonists and inhibitors;抗胆固醇血症药;酶抑制剂;吡啶类;尿素;

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1. Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-((fluorophenoxy)benzyl)-N'-arylureas with weak toxicological effects on adrenal glands. [J] . Tanaka A, Terasawa T, Hagihara H, Journal of Medicinal Chemistry . 1998,第22期

机译：酰基辅酶A抑制剂：胆固醇O-酰基转移酶。 3.发现对肾上腺具有弱毒理学作用的一系列新的N-烷基-N-（（氟苯氧基）苄基）-N'-芳基脲。
2. Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT). Part 1: identification and structure-activity relationships of a novel series of substituted N-alkyl-N-biphenylylmethyl-N'-arylureas. [J] . Tanaka A, Terasawa T, Hagihara H, Bioorganic and medicinal chemistry . 1998,第1期

机译：酰基辅酶A：胆固醇O-酰基转移酶（ACAT）的抑制剂。第1部分：一系列新的取代的N-烷基-N-联苯基甲基-N'-芳基脲的鉴定与构效关系。
3. Discovery of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: The Synthesis, Biological Evaluation, and Reduced Adrenal Toxicity of (4-Phenylcoumarin)acetanilide Derivatives with a Carboxylic Acid Moiety [J] . Chemical and Pharmaceutical Bulletin . 2011,第11期

机译：新型酰基辅酶A的发现：胆固醇酰基转移酶抑制剂：（4-苯基香豆素）乙苯胺衍生物与羧酸部分的合成，生物学评估和降低的肾上腺毒性。
4. AN ULTRASTRUCTURAL AND BIOCHEMICAL STUDY OF THE EFFECTS OF THREE INHIBITORS OF CHOLESTEROL BIOSYNTHESIS UPON MURINE ADRENAL GLAND AND TESTIS [O] . Scott E. Dietert, Terence J. Scallen 1969

机译：三种胆固醇抑制剂对小鼠肾上腺和睾丸胆固醇合成的超微结构和生物化学研究
5. Discovery of a Novel Acyl-CoA: Cholesterol Acyltransferase Inhibitor: The Synthesis, Biological Evaluation, and Reduced Adrenal Toxicity of (4-Phenylcoumarin)acetanilide Derivatives with a Carboxylic Acid Moiety [O] . Masaki Ogino, Yoshihisa Nakada, Nobuyuki Negoro, 2011

机译：发现新型酰基-CoA：胆固醇酰基转移酶抑制剂：用羧酸部分（4-苯基苏格林）乙酰苯胺衍生物的合成，生物学评价和降低的肾上腺毒性

Inhibitors of acyl-CoA:cholesterol O-acyltransferase. 3. Discovery of a novel series of N-alkyl-N-((fluorophenoxy)benzyl)-N'-arylureas with weak toxicological effects on adrenal glands.

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