Synthesis and structure-activity relationships of novel IKK-beta inhibitors. Part 3: Orally active anti-inflammatory agents.
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).
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
Sakakibara
Sachiko
S
Yoshino
Takashi
T
Masuda
Tsutomu
T
Shintani
Takuya
T
Sato
Hiroki
H
Koriyama
Yuji
Y
Fukushima
Keiko
K
Nunami
Noriko
N
Yamauchi
Megumi
M
Fuchikami
Kinji
K
Komura
Hiroshi
H
Watanabe
Akihiko
A
Ziegelbauer
Karl B
KB
Bacon
Kevin B
KB
Lowinger
Timothy B
TB
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
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