(PYRIMIDINYLOXY)ACETIC ACIDS AND PYRIMIDINEACETIC ACIDS AS A NOVEL CLASS OF ALDOSE REDUCTASE INHIBITORS

被引：20

作者：

ELLINGBOE, J ^{[1
]}

ALESSI, T ^{[1
]}

MILLEN, J ^{[1
]}

SREDY, J ^{[1
]}

KING, A ^{[1
]}

PRUSIEWICZ, C ^{[1
]}

GUZZO, F ^{[1
]}

VANENGEN, D ^{[1
]}

BAGLI, J ^{[1
]}

机构：

[1] PRINCETON UNIV, PRINCETON, NJ 08544 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1990年 / 33卷 / 10期

关键词：

D O I：

10.1021/jm00172a034

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pyrimidineacetic acids and (pyrimidinyloxy)acetic acids were synthesized by alkylation, with methyl bromoacetate or tert-butyl bromoacetate as alkylating agents. Alkylation reaction at the nitrogen or oxygen atom for different substrates was found to be solvent dependent. N-Alkylation was favored in ethereal solvent, e.g., tetrahydrofuran and dimethoxyethane, whereas O-alkylation was predominant in dimethylformamide. These compounds were tested in vitro to determine their ability to inhibit bovine lens aldose reductase. Selected compounds were assayed in vivo, in a 4-day galactose-fed rat model. The decrease in galactitol from the control was determined in lens, nerve, and diaphragm. Several of the 6-oxopyrimidine-l-acetic acids and (pyrimidinyl-4-oxy)acetic acids were found to be potent inhibitors of bovine lens aldose reductase. A study was also undertaken to determine in vitro the transport behavior of selected compounds in the isolated rat sciatic nerve. A discussion of the structure-activity relationship of this class of compounds with reference to their intrinsic biochemical activity is reported. It is concluded, in general, that ability of a compound to penetrate the tissue membrane plays an important role in the genesis of in vivo lens aldose reductase (LAR) inhibitory activity. © 1990, American Chemical Society. All rights reserved.

引用

页码：2892 / 2899

页数：8

共 18 条

[1] CHEMISTRY AND POSITIVE INOTROPIC EFFECT OF PELRINONE AND RELATED DERIVATIVES - A NOVEL CLASS OF 2-METHYLPYRIMIDONES AS INOTROPIC AGENTS [J].