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
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
收藏
页码:1219 / 1233
页数:15
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