1. 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.
- Author
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Green N, Hu Y, Janz K, Li HQ, Kaila N, Guler S, Thomason J, Joseph-McCarthy D, Tam SY, Hotchandani R, Wu J, Huang A, Wang Q, Leung L, Pelker J, Marusic S, Hsu S, Telliez JB, Hall JP, Cuozzo JW, and Lin LL
- Subjects
- Aminoquinolines pharmacokinetics, Aminoquinolines pharmacology, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Crystallography, X-Ray, ErbB Receptors antagonists & inhibitors, ErbB Receptors chemistry, Erlotinib Hydrochloride, Female, Humans, Imidazoles pharmacokinetics, Imidazoles pharmacology, In Vitro Techniques, MAP Kinase Kinase Kinases biosynthesis, MAP Kinase Kinase Kinases chemistry, Microsomes, Liver metabolism, Protein Structure, Tertiary, Proto-Oncogene Proteins biosynthesis, Proto-Oncogene Proteins chemistry, Quinazolines chemistry, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Tumor Necrosis Factor-alpha biosynthesis, Tumor Necrosis Factor-alpha chemistry, Aminoquinolines chemical synthesis, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Imidazoles chemical synthesis, MAP Kinase Kinase Kinases antagonists & inhibitors, Models, Molecular, Proto-Oncogene Proteins antagonists & inhibitors, Tumor Necrosis Factor-alpha antagonists & inhibitors
- 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.
- Published
- 2007
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