Identification of an Adamantyl Azaquinolone JNK Selective Inhibitor

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• 作者：Nancy-Ellen Haynes ; Nathan R. Scott ; Li C. Chen ; Cheryl A. Janson ; Jia Kui Li ; Christine M. Lukacs ; Aruna Railkar ; Effie Tozzo ; Toni Whittard ; Nicholas F. Brown ; Adrian Wai-Hing Cheung
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：September 13, 2012
• 年：2012
• 卷：3
• 期：9
• 页码：764-768
• 全文大小：349K
• 年卷期：v.3,no.9(September 13, 2012)
• ISSN：1948-5875

文摘

3-[4-((1S,2S,3R,5S,7S)-5-Hydroxyadamantan-2-ylcarbamoyl)benzyl]-4-oxo-1-phenyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (4) was identified as a novel, druglike and selective quinolone pan JNK inhibitor. In this communication, some of the structure鈥揳ctivity relationship of the azaquinolone analogues leading to 4 is discussed. The focus is on how changes at the amide functionality affected the biochemical potency, cellular potency, metabolic properties, and solubility of this class of JNK inhibitors. Optimization of these properties led to the identification of the adamantyl analogue, 4. 4 achieved proof of mechanism in both rat and mouse TNF-伪 challenge models.

Keywords:

JNK selective inhibitor; kidney disease; adamantyl azaquinolone