title: Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles.
abstract: Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.
authors: Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. ngreen@wyeth.com
authors: Neal
authors: N
authors: Green
authors: Yonghan
authors: Y
authors: Hu
authors: Kristin
authors: K
authors: Janz
authors: Huan-Qiu
authors: HQ
authors: Li
authors: Neelu
authors: N
authors: Kaila
authors: Satenig
authors: S
authors: Guler
authors: Jennifer
authors: J
authors: Thomason
authors: Diane
authors: D
authors: Joseph-McCarthy
authors: Steve Y
authors: SY
authors: Tam
authors: Rajeev
authors: R
authors: Hotchandani
authors: Junjun
authors: J
authors: Wu
authors: Adrian
authors: A
authors: Huang
authors: Qin
authors: Q
authors: Wang
authors: Louis
authors: L
authors: Leung
authors: Jefferey
authors: J
authors: Pelker
authors: Suzana
authors: S
authors: Marusic
authors: Sang
authors: S
authors: Hsu
authors: Jean-Baptiste
authors: JB
authors: Telliez
authors: J Perry
authors: JP
authors: Hall
authors: John W
authors: JW
authors: Cuozzo
authors: Lih-Ling
authors: LL
authors: Lin
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry
chemical_list: C523631:8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1-methyl-1H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile; D000634:Aminoquinolines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human