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

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.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Kaila N,Green N,Li HQ,Hu Y,Janz K,Gavrin LK,Thomason J,Tam S,Powell D,Cuozzo J,Hall JP,Telliez JB,Hsu S,Nickerson-Nutter C,Wang Q,Lin LL

doi

10.1016/j.bmc.2007.06.054

subject

Has Abstract

pub_date

2007-10-01 00:00:00

pages

6425-42

issue

19

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(07)00590-1

journal_volume

15

pub_type

杂志文章

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