5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives as potent and selective transforming growth factor-β type I receptor inhibitors

被引：18
作者：
Amada, Hideaki [1 ]
Sekiguchi, Yoshinori [1 ]
Ono, Naoya [1 ]
Koami, Takeshi [1 ]
Takayama, Tetsuo [1 ]
Yabuuchi, Tetsuya [1 ]
Katakai, Hironori [1 ]
Ikeda, Akiko [2 ]
Aoki, Mari [2 ]
Naruse, Takumi [2 ]
Wada, Reiko [2 ]
Nozoe, Akiko [3 ]
Sato, Masakazu [1 ]
机构：
[1] Taisho Pharmaceut Co Ltd, Med Chem Labs, Kita Ku, Saitama 3319530, Japan
[2] Taisho Pharmaceut Co Ltd, Mol Funct & Pharmacol Labs, Kita Ku, Saitama 3319530, Japan
[3] Taisho Pharmaceut Co Ltd, Pharmaceut Technol Labs, Kita Ku, Saitama 3319530, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2012年 / 20卷 / 24期
关键词：
ALK5; inhibitor; Transforming growth factor-beta; Solubility; Topical application; Alopecia; TGF-BETA; HAIR-FOLLICLES; CELL-MEMBRANE; IDENTIFICATION; DESIGN; ALK5;
D O I：
10.1016/j.bmc.2012.09.066
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：
A series of 5-(1,3-benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazole derivatives was synthesized as transforming growth factor-beta (TGF-beta) type I receptor (also known as activin-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and for their TGF-beta-induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. As a representative compound, 16i was a potent and selective ALK5 inhibitor, exhibiting a good enzyme inhibitory activity (IC50 = 5.5 nM) as well as inhibitory activity against TGF-beta-induced Smad2/3 phosphorylation at a cellular level (IC50 = 36 nM). Furthermore, the topical application of 3% 16i lotion significantly inhibited Smad2 phosphorylation in Mouse skin (90% inhibition compared with vehicle-treated animals). (C) 2012 Elsevier Ltd. All rights reserved.
引用
收藏
页码：7128 / 7138
页数：11
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