Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H1 antagonists

被引：37
|
作者：
Kubota, Katsumi [1 ]
Kurebayashi, Hirotaka [1 ]
Miyachi, Hirotaka [1 ]
Tobe, Masanori [1 ]
Onishi, Masako [1 ]
Isobe, Yoshiaki [1 ]
机构：
[1] Dainippon Sumitomo Phrama Co Ltd, Konohana ku, Osaka 5540022, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 10期
关键词：
Histamine; H-1; Antagonist; Phenothiazine; Carboxylic acid; Pyrimidine-dione; HYPERSENSITIVITY REACTION; CX-659S; CELLS; TAK-427; MODEL;
D O I：
10.1016/j.bmcl.2009.03.124
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, were synthesized and evaluated for their affinity toward human histamine H-1 receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H-1-receptor antagonistic activity and anti-inflammatory activity in vivo model. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码：2766 / 2771
页数：6
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