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

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

Affiliation

  • 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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