title: Selective inhibitors of tumor progression loci-2 (Tpl2) kinase with potent inhibition of TNF-alpha production in human whole blood.
abstract: 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.
authors.affiliation: Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. jjwu@wyeth.com
authors.forename: Junjun
authors.initials: J
authors.lastname: Wu
authors.forename: Neal
authors.initials: N
authors.lastname: Green
authors.forename: Rajeev
authors.initials: R
authors.lastname: Hotchandani
authors.forename: Yonghan
authors.initials: Y
authors.lastname: Hu
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Condon
authors.forename: Adrian
authors.initials: A
authors.lastname: Huang
authors.forename: Neelu
authors.initials: N
authors.lastname: Kaila
authors.forename: Huan-Qiu
authors.initials: HQ
authors.lastname: Li
authors.forename: Satenig
authors.initials: S
authors.lastname: Guler
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Steve Y
authors.initials: SY
authors.lastname: Tam
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Pelker
authors.forename: Suzana
authors.initials: S
authors.lastname: Marusic
authors.forename: Sang
authors.initials: S
authors.lastname: Hsu
authors.forename: J
authors.initials: J
authors.lastname: Perry Hall
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
authors.forename: Junqing
authors.initials: J
authors.lastname: Cui
authors.forename: Lih-Ling
authors.initials: LL
authors.lastname: Lin
mesh_terms: 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*
chemical_list: 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