Synthesis and structure-activity relationships of novel IKK-β inhibitors.: Part 3:: Orally active anti-inflammatory agents

被引：116
|
作者：
Murata, T [1 ]
Shimada, M
Sakakibara, S
Yoshino, T
Masuda, T
Shintani, T
Sato, H
Koriyama, Y
Fukushima, K
Nunami, N
Yamauchi, M
Fuchikami, K
Komura, H
Watanabe, A
Ziegelbauer, KB
Bacon, KB
Lowinger, TB
机构：
[1] Bayer Yakuhin Ltd, Res Ctr Kyoto, Dept Chem, Sora Ku, Kyoto 6190216, Japan
[2] Bayer Yakuhin Ltd, Res Ctr Kyoto, Dept Biol, Sora Ku, Kyoto 6190216, Japan
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2004年 / 14卷 / 15期
关键词：
IKK-beta; NF-kappa B; kinase inhibitor;
D O I：
10.1016/j.bmcl.2004.05.041
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IkappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC50 = 1500 nM, Cell IC50 = 8000 nM) at the 4-phenyl ring and 6-phenol group on the pyridine core ring resulted in a marked increased in biological activities. An optimized compound, 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-yl nicotinonitrile, exhibited excellent in vitro profiles (IKK-beta IC50 = 8.5 nM, Cell IC50 = 60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1 mg/kg, po in arachidonic acid-induced ear edema model in mice). (C) 2004 Elsevier Ltd. All rights reserved.
引用
收藏
页码：4019 / 4022
页数：4
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