Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.
Tpl2 (cot/MAP3K8) is an upstream kinase of MEK in the ERK pathway. It plays an important role in Tumor Necrosis Factor-alpha (TNF-alpha) production and signaling. We have discovered that 8-halo-4-(3-chloro-4-fluoro-phenylamino)-6-[(1H-[1,2,3]triazol-4-ylmethyl)-amino]-quinoline-3-carbonitriles (4) are potent inhibitors of this enzyme. In order to improve the inhibition of TNF-alpha production in LPS-stimulated human blood, a series of analogs with a variety of substitutions around the triazole moiety were studied. We found that a cyclic amine group appended to the triazole ring could considerably enhance potency, aqueous solubility, and cell membrane permeability. Optimization of these cyclic amine groups led to the identification of 8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile (34). In a LPS-stimulated rat inflammation model, compound 34 showed good efficacy in inhibiting TNF-alpha production.
Wu
Junjun
J
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. jjwu@wyeth.com
Green
Neal
N
Hotchandani
Rajeev
R
Hu
Yonghan
Y
Condon
Jeffrey
J
Huang
Adrian
A
Kaila
Neelu
N
Li
Huan-Qiu
HQ
Guler
Satenig
S
Li
Wei
W
Tam
Steve Y
SY
Wang
Qin
Q
Pelker
Jeffrey
J
Marusic
Suzana
S
Hsu
Sang
S
Perry Hall
J
J
Telliez
Jean-Baptiste
JB
Cui
Junqing
J
Lin
Lih-Ling
LL
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood*
C542866:8-chloro-4-(3-chloro-4-fluorophenylamino)-6-((1-(1-ethylpiperidin-4-yl)-1H-1,2,3-triazol-4-yl)methylamino)quinoline-3-carbonitrile; D000893:Anti-Inflammatory Agents; D008070:Lipopolysaccharides; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011804:Quinolines; D014409:Tumor Necrosis Factor-alpha; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human