Author/Authors :
Toshiki Murata، نويسنده , , Mitsuyuki Shimada، نويسنده , , Sachiko Sakakibara، نويسنده , , Takashi Yoshino ، نويسنده , , Tsutomu Masuda، نويسنده , , Takuya Shintani، نويسنده , , Hiroki Sato، نويسنده , , Yuji Koriyama، نويسنده , , Keiko Fukushima، نويسنده , , Noriko Nunami، نويسنده , , Megumi Yamauchi، نويسنده , , Kinji Fuchikami، نويسنده , , Hiroshi Komura، نويسنده , , Akihiko Watanabe، نويسنده , , Karl B. Ziegelbauer، نويسنده , , Kevin B. Bacon، نويسنده , , Timothy B. Lowinger، نويسنده ,
Abstract :
A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as IκB kinase β (IKK-β) inhibitors. Modification of a novel IKK-β inhibitor 1 (IKK-β 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-β 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).
Keywords :
IKK-b , NF-jB , Kinase inhibitor.* Corresponding author. Tel.: +81-774-75-2483 , fax: +81-774-75-2510 , e-mail: muratato@kcn.ne.jp
