Identification of a novel class of selective Tpl2 kinase inhibitors: 4-Alkylamino-[1,7]naphthyridine-3-carbonitriles.
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.
Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. nkaila@wyeth.com
Neelu
N
Kaila
Neal
N
Green
Huan-Qiu
HQ
Li
Yonghan
Y
Hu
Kristin
K
Janz
Lori Krim
LK
Gavrin
Jennifer
J
Thomason
Steve
S
Tam
Dennis
D
Powell
John
J
Cuozzo
J Perry
JP
Hall
Jean-Baptiste
JB
Telliez
Sang
S
Hsu
Cheryl
C
Nickerson-Nutter
Qin
Q
Wang
Lih-Ling
LL
Lin
D000818:Animals; D001667:Binding, Competitive; D003508:Cycloheptanes / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D000099190:MAP-Kinase-Activated Kinase 2
D003508:Cycloheptanes; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009287:Naphthyridines; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C034591:cycloheptylamine; C080356:Map3k8 protein, rat