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

被引：117

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

页码：4019 / 4022

页数：4

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