Discovery and structure-guided optimization of tert-butyl 6-(phenoxymethyl)-3-(trifluoromethyl)benzoates as liver X receptor agonists

被引：11

作者：

Matsui, Yumi ^{[1
]}

Yamaguchi, Takahiro ^{[2
]}

Yamazaki, Takanori ^{[2
]}

Yoshida, Masayuki ^{[2
]}

Arai, Masami ^{[2
]}

Terasaka, Naoki ^{[2
]}

Honzumi, Shoko ^{[2
]}

Wakabayashi, Kenji ^{[1
]}

Hayashi, Shinko ^{[2
]}

Nakai, Daisuke ^{[2
]}

Hanzawa, Hiroyuki ^{[1
]}

Tamaki, Kazuhiko ^{[2
]}

机构：

[1] Daiichi Sankyo RD Novare Co Ltd, Edogawa Ku, Tokyo 1348630, Japan

[2] Daiichi Sankyo Co Ltd, R&D Div, Shinagawa Ku, Tokyo 1408710, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2015年 / 25卷 / 18期

关键词：

Liver X receptors; LXR agonists; Atherosclerosis; tert-Butyl benzoate; Structure-based drug design; CELLULAR CHOLESTEROL EFFLUX; MITSUNOBU REACTION; NUCLEAR-RECEPTOR; LXR-ALPHA; LIGAND; ATHEROSCLEROSIS; MICE; EXPRESSION; REAGENT; AMINES;

D O I：

10.1016/j.bmcl.2015.07.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To obtain potent liver X receptor (LXR) agonists, a structure-activity relationship study was performed on a series of tert-butyl benzoate analogs. As the crystal structure analysis suggested applicable interactions between the LXR ligand-binding domain and the ligands, two key functional groups were introduced. The introduction of the hydroxyl group on the C6-position of the benzoate part enhanced the agonistic activity in a cell-based assay, and the carboxyl group in terminal improved the pharmacokinetic profile in mice, respectively. The obtained compound 32b increased blood ABCA1 mRNA expression without plasma TG elevation in both mice and cynomolgus monkeys. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：3914 / 3920

页数：7

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