title: Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity.
abstract: 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. Substitution of an aminoalkyl group for the aromatic group at the 4-position on the core pyridine ring resulted in a marked increase in both kinase enzyme and cellular potencies, and provided potent IKK-beta inhibitors with IC(50) values of below 100 nM.
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: Hiroshi
authors.initials: H
authors.lastname: Kadono
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: Makoto
authors.initials: M
authors.lastname: Shimazaki
authors.forename: Takuya
authors.initials: T
authors.lastname: Shintani
authors.forename: Kinji
authors.initials: K
authors.lastname: Fuchikami
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Bacon
authors.forename: Karl B
authors.initials: KB
authors.lastname: Ziegelbauer
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Lowinger
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051550:I-kappa B Kinase; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human