Synthesis and SAR study of new thiazole derivatives as vascular adhesion protein-1 (VAP-1) inhibitors for the treatment of diabetic macular edema

被引：14

作者：

Inoue, Takayuki ^{[1
]}

Morita, Masataka ^{[1
]}

Tojo, Takashi ^{[1
]}

Yoshihara, Kousei ^{[1
]}

Nagashima, Akira ^{[1
]}

Moritomo, Ayako ^{[1
]}

Ohkubo, Mitsuru ^{[2
]}

Miyake, Hiroshi ^{[2
]}

机构：

[1] Astellas Pharma Inc, Drug Discovery Res, Tsukuba, Ibaraki 3058585, Japan

[2] Astellas Res Technol Inc, Tsukuba, Ibaraki 3058585, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 05期

关键词：

VAP-1; Inhibitor; Macular edema; Thiazole; Guanidine; SENSITIVE AMINE OXIDASE; INVOLVEMENT; MELLITUS;

D O I：

10.1016/j.bmc.2012.12.025

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Vascular adhesion protein-1 (VAP-1), an amine oxidase that is also known as a semicarbazide-sensitive amine oxidase (SSAO), is present in particularly high levels in human plasma, and is considered a potential therapeutic target for various inflammatory diseases, including diabetes complications such as macular edema. In our VAP-1 inhibitor program, structural modifications following high-throughput screening (HTS) of our compound library resulted in the discovery that thiazole derivative 10, which includes a guanidine group, shows potent human VAP-1 inhibitory activity (IC50 of 230 nM; rat IC50 of 14 nM). Moreover, compound 10 exhibited significant inhibitory effects on ocular permeability in STZ-induced diabetic rats. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：1219 / 1233

页数：15

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