A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation.
Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (K(i) = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFalpha production with similar activity (IC(50) = 160 nM). PF-3644022 blocks TNFalpha and IL-6 production in LPS-stimulated human whole blood with IC(50) values of 1.6 and 10.3 microM, respectively. Inhibition of TNFalpha in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFalpha model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFalpha production in the acute model and inhibition of paw swelling in the chronic model is observed with ED(50) values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C(min) higher than the EC(50) measured in the rat LPS-induced TNFalpha model.
Department of Discovery Biology, Inflammation Research Unit, Pfizer Global Research and Development, Chesterfield, Missouri, USA.
Robert J
RJ
Mourey
Barry L
BL
Burnette
Sarah J
SJ
Brustkern
J Scott
JS
Daniels
Jeffrey L
JL
Hirsch
William F
WF
Hood
Marvin J
MJ
Meyers
Stephen J
SJ
Mnich
Betsy S
BS
Pierce
Matthew J
MJ
Saabye
John F
JF
Schindler
Sarah A
SA
South
Elizabeth G
EG
Webb
Jian
J
Zhang
David R
DR
Anderson
D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology; D001667:Binding, Competitive / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D005260:Female; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013291:Streptococcus; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D020298:U937 Cells; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors
C549914:10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-(1,4)diazepino(5',6'-4,5)thieno(3,2-f)quinolin-8-one; D000893:Anti-Inflammatory Agents; D006576:Heterocyclic Compounds, 4 or More Rings; D008070:Lipopolysaccharides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D019950:Mitogen-Activated Protein Kinase 1; D048051:p38 Mitogen-Activated Protein Kinases