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

被引：40

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

页码：2766 / 2771

页数：6

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