Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors.
Analog 8, a 3-pyridinecarbonitrile with an (E)-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]vinyl group at C-5, had an IC(50) value of 1.1 nM for the inhibition of PKCtheta and potently blocked the production of IL-2 in both stimulated murine T cells (IC(50)=34 nM) and human whole blood (IC(50)=500 nM).
Wyeth Research, Pearl River, NY 10965, USA. bosched@wyeth.com
Diane H
DH
Boschelli
Joan
J
Subrath
Chuansheng
C
Niu
Biqi
B
Wu
Yan
Y
Wang
Julie
J
Lee
Agnes
A
Brennan
Melisa
M
Ho
Bijia
B
Deng
Xiaoke
X
Yang
Xin
X
Xu
Louis
L
Leung
Jianyao
J
Wang
James
J
Atherton
Divya
D
Chaudhary
D000818:Animals; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009570:Nitriles / Q000737:chemistry / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
D007376:Interleukin-2; D007527:Isoenzymes; D009570:Nitriles; D047428:Protein Kinase Inhibitors; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta