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Junjun Wu,
Neal Green,
Rajeev Hotchandani,
Yonghan Hu,
Jeffrey Condon,
Adrian Huang,
Neelu Kaila, Huan-Qiu Li,
Satenig Guler,
Wei Li,
Steve Y Tam,
Qin Wang,
Jeffrey Pelker,
Suzana Marusic,
Sang Hsu,
J Perry Hall,
Jean-Baptiste Telliez,
Junqing Cui,
Lih-Ling Lin
[show abstract]
[hide abstract]
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.
Bioorganic & medicinal chemistry letters 08/2009; 19(13):3485-8. · 2.65 Impact Factor
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Neelu Kaila,
Neal Green, Huan-Qiu Li,
Yonghan Hu,
Kristin Janz,
Lori Krim Gavrin,
Jennifer Thomason,
Steve Tam,
Dennis Powell,
John Cuozzo,
J Perry Hall,
Jean-Baptiste Telliez,
Sang Hsu,
Cheryl Nickerson-Nutter,
Qin Wang,
Lih-Ling Lin
[show abstract]
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ABSTRACT: We have previously reported the discovery and initial SAR of the [1,7]naphthyridine-3-carbonitriles and quinoline-3-carbonitriles as Tumor Progression Loci-2 (Tpl2) kinase inhibitors. In this paper, we report new SAR efforts which have led to the identification of 4-alkylamino-[1,7]naphthyridine-3-carbonitriles. These compounds show good in vitro and in vivo activity against Tpl2 and improved pharmacokinetic properties. In addition they are highly selective for Tpl2 kinase over other kinases, for example, EGFR, MEK, MK2, and p38. Lead compound 4-cycloheptylamino-6-[(pyridin-3-ylmethyl)-amino]-[1,7]naphthyridine-3-carbonitrile (30) was efficacious in a rat model of LPS-induced TNF-alpha production.
Bioorganic & Medicinal Chemistry 11/2007; 15(19):6425-42. · 2.92 Impact Factor
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Neal Green,
Yonghan Hu,
Kristin Janz, Huan-Qiu Li,
Neelu Kaila,
Satenig Guler,
Jennifer Thomason,
Diane Joseph-McCarthy,
Steve Y Tam,
Rajeev Hotchandani, [......],
Adrian Huang,
Qin Wang,
Louis Leung,
Jefferey Pelker,
Suzana Marusic,
Sang Hsu,
Jean-Baptiste Telliez,
J Perry Hall,
John W Cuozzo,
Lih-Ling Lin
[show abstract]
[hide abstract]
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.
Journal of Medicinal Chemistry 10/2007; 50(19):4728-45. · 5.25 Impact Factor
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Yonghan Hu,
Neal Green,
Lori K Gavrin,
Kristin Janz,
Neelu Kaila, Huan-Qiu Li,
Jennifer R Thomason,
John W Cuozzo,
J Perry Hall,
Sang Hsu,
Cheryl Nickerson-Nutter,
Jean-Baptiste Telliez,
Lih-Ling Lin,
Steve Tam
[show abstract]
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ABSTRACT: The synthesis and structure-activity studies of a series of quinoline-3-carbonitriles as inhibitors of Tpl2 kinase are described. Potent inhibitors of Tpl2 kinase with selectivity against a panel of selected kinases in enzymatic assays and specificity in cell-based phosphorylation assays in LPS-treated human monocytes were identified. Selected inhibitors with moderate activity in human whole blood assay effectively inhibited LPS/D-Gal induced TNFalpha release when administered intraperitoneally in mice.
Bioorganic & Medicinal Chemistry Letters 01/2007; 16(23):6067-72. · 2.55 Impact Factor
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Lori Krim Gavrin,
Neal Green,
Yonghan Hu,
Kristin Janz,
Neelu Kaila, Huan-Qiu Li,
Steve Y Tam,
Jennifer R Thomason,
Ariamala Gopalsamy,
Greg Ciszewski,
John W Cuozzo,
J Perry Hall,
Sang Hsu,
Jean-Baptiste Telliez,
Lih-Ling Lin
[show abstract]
[hide abstract]
ABSTRACT: The synthesis and structure-activity studies of a series of 6-substituted-4-anilino-[1,7]-naphthyridine-3-carbonitriles as inhibitors of Tpl2 kinase are described. The early exploratory work described here may lead to the discovery of compounds with significant therapeutic potential for treating rheumatoid arthritis and other inflammatory diseases.
Bioorganic & Medicinal Chemistry Letters 01/2006; 15(23):5288-92. · 2.55 Impact Factor
