Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 2: Improvement of in vitro activity.
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.
Murata
Toshiki
T
Department of Chemistry, Research Center Kyoto, Bayer Yakuhin Ltd., Kizu, Soraku, Kyoto 619-0216, Japan. muratato@kcn.ne.jp
Shimada
Mitsuyuki
M
Kadono
Hiroshi
H
Sakakibara
Sachiko
S
Yoshino
Takashi
T
Masuda
Tsutomu
T
Shimazaki
Makoto
M
Shintani
Takuya
T
Fuchikami
Kinji
K
Bacon
Kevin B
KB
Ziegelbauer
Karl B
KB
Lowinger
Timothy B
TB
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
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