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

  • Bioorg Med Chem Lett. 2004 Aug 2;14(15):4019-22. doi: 10.1016/j.bmcl.2004.05.041.
Toshiki Murata  1 ,  Mitsuyuki Shimada ,  Sachiko Sakakibara ,  Takashi Yoshino ,  Tsutomu Masuda ,  Takuya Shintani ,  Hiroki Sato ,  Yuji Koriyama ,  Keiko Fukushima ,  Noriko Nunami ,  Megumi Yamauchi ,  Kinji Fuchikami ,  Hiroshi Komura ,  Akihiko Watanabe ,  Karl B Ziegelbauer ,  Kevin B Bacon ,  Timothy B Lowinger
Affiliations
  • 1. Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan. [email protected]
PMID: 15225718 DOI: 10.1016/j.bmcl.2004.05.041
Abstract

A series of 2-amino-3-cyano-4-alkyl-6-(2-hydroxyphenyl)pyridine derivatives was synthesized and evaluated as I kappaB kinase beta (IKK-beta) inhibitors. Modification of a novel IKK-beta inhibitor 1 (IKK-beta IC(50)=1500 nM, Cell IC(50)=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 IC(50)=8.5 nM, Cell IC(50)=60 nM) and a strong oral efficacy in in vivo anti-inflammatory assays (significant effects at 1mg/kg, po in arachidonic acid-induced ear edema model in mice).

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