Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles
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- 作者：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 Nicke
- 关键词：Tpl2 kinase ; [1 ; 7]Naphthyridine-3-carbonitriles ; Quinoline-3-carbonitriles
- 刊名：Bioorganic and Medicinal Chemistry
- 出版年：2007
- 出版时间：1 October 2007
- 年：2007
- 卷：15
- 期：19
- 页码：6425-6442
- 全文大小：564 K
文摘
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-α production.