title: Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents.
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).
authors.affiliation: Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan. muratato@kcn.ne.jp
authors.forename: Toshiki
authors.initials: T
authors.lastname: Murata
authors.forename: Mitsuyuki
authors.initials: M
authors.lastname: Shimada
authors.forename: Sachiko
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masuda
authors.forename: Takuya
authors.initials: T
authors.lastname: Shintani
authors.forename: Hiroki
authors.initials: H
authors.lastname: Sato
authors.forename: Yuji
authors.initials: Y
authors.lastname: Koriyama
authors.forename: Keiko
authors.initials: K
authors.lastname: Fukushima
authors.forename: Noriko
authors.initials: N
authors.lastname: Nunami
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamauchi
authors.forename: Kinji
authors.initials: K
authors.lastname: Fuchikami
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Komura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Watanabe
authors.forename: Karl B
authors.initials: KB
authors.lastname: Ziegelbauer
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Lowinger
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D004487:Edema / Q000517:prevention & control; D006801:Humans; D051550:I-kappa B Kinase; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D011725:Pyridines; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse