Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles.

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

文献索引：Bioorg. Med. Chem. 15(19) , 6425-42, (2007)

全文：HTML全文

摘要

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.