Optimization of 5-vinylaryl-3-pyridinecarbonitriles as PKCtheta inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 6; pp. 1965 - 1968
• Main Authors: Boschelli, Diane H, Subrath, Joan, Niu, Chuansheng, Wu, Biqi, Wang, Yan, Lee, Julie, Brennan, Agnes, Ho, Melisa, Deng, Bijia, Yang, Xiaoke, Xu, Xin, Leung, Louis, Wang, Jianyao, Atherton, James, Chaudhary, Divya
• Format: Journal Article
• Language: English
• Published: England 15.03.2010
• Subjects: Animals; Humans; Interleukin-2 - biosynthesis; Isoenzymes - antagonists & inhibitors; Mice; Microsomes, Liver - drug effects; Microsomes, Liver - enzymology; Nitriles - chemistry; Nitriles - pharmacology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C-theta; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2010.01.119

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).