Author/Authors :
Neelu Kaila، نويسنده , , Neal Green، نويسنده , , Huan-Qiu Li، نويسنده , , Yonghan Hu، نويسنده , , Kristin Janz، نويسنده , , Lori Krim Gavrin، نويسنده , , Jennifer Thomason، نويسنده , , Steve Tam، نويسنده , , Dennis Powell، نويسنده , , John Cuozzo، نويسنده , , J. Perry Hall، نويسنده , , Jean-Baptiste Telliez، نويسنده , , Sang Hsu، نويسنده , , Cheryl Nickerson-Nutter، نويسنده , , Qin Wang، نويسنده , , Lih-Ling Lin، نويسنده ,
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-α production.
Keywords :
1 , 7]Naphthyridine-3-carbonitriles , Tpl2 kinase , Quinoline-3-carbonitriles
