Inhibitors of tumor progression loci-2 (Tpl2) kinase and tumor necrosis factor alpha (TNF-alpha) production: selectivity and in vivo antiinflammatory activity of novel 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles.
Tumor progression loci-2 (Tpl2) (Cot/MAP3K8) is a serine/threonine kinase in the MAP3K family directly upstream of MEK. Recent studies using Tpl2 knockout mice have indicated an important role for Tpl2 in the lipopolysaccharide (LPS) induced production of tumor necrosis factor alpha (TNF-alpha) and other proinflammatory cytokines involved in diseases such as rheumatoid arthritis. Initial 4-anilino-6-aminoquinoline-3-carbonitrile leads showed poor selectivity for Tpl2 over epidermal growth factor receptor (EGFR) kinase. Using molecular modeling and crystallographic data of the EGFR kinase domain with and without an EGFR kinase-specific 4-anilinoquinazoline inhibitor (erlotinib, Tarceva), we hypothesized that we could diminish the inhibition of EGFR kinase by substitution at the C-8 position of our 4-anilino-6-aminoquinoline-3-carbonitrile leads. The 8-substituted-4-anilino-6-aminoquinoline-3-carbonitriles were prepared from the appropriate 2-substituted 4-nitroanilines. Modifications to the C-6 and C-8 positions led to the identification of compounds with increased inhibition of TNF-alpha release from LPS-stimulated rat and human blood, and these analogues were also highly selective for Tpl2 kinase over EGFR kinase. Further structure-activity based modifications led to the identification of 8-bromo-4-(3-chloro-4-fluorophenylamino)-6-[(1-methyl-1H-imidazol-4-yl)methylamino]quinoline-3-carbonitrile, which demonstrated in vitro as well as in vivo efficacy in inhibition of LPS-induced TNF-alpha production.
Green
Neal
N
Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, Massachusetts 02140, USA. ngreen@wyeth.com
Hu
Yonghan
Y
Janz
Kristin
K
Li
Huan-Qiu
HQ
Kaila
Neelu
N
Guler
Satenig
S
Thomason
Jennifer
J
Joseph-McCarthy
Diane
D
Tam
Steve Y
SY
Hotchandani
Rajeev
R
Wu
Junjun
J
Huang
Adrian
A
Wang
Qin
Q
Leung
Louis
L
Pelker
Jefferey
J
Marusic
Suzana
S
Hsu
Sang
S
Telliez
Jean-Baptiste
JB
Hall
J Perry
JP
Cuozzo
John W
JW
Lin
Lih-Ling
LL
D000634:Aminoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000737:chemistry; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D066298:In Vitro Techniques; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D011799:Quinazolines / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry
C523631:8-bromo-4-(3-chloro-4-fluorophenylamino)-6-((1-methyl-1H-imidazol-4-yl)methylamino)quinoline-3-carbonitrile; D000634:Aminoquinolines; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D014409:Tumor Necrosis Factor-alpha; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human