| Autor: |
W. Martin, Matthew, Newcomb, John, J. Nunes, Joseph, C. McGowan, David, M. Armistead, David, Boucher, Christina, L. Buchanan, John, Buckner, William, Chai, Lilly, Elbaum, Daniel, F. Epstein, Linda, Faust, Theodore, Flynn, Shaun, Gallant, Paul, Gore, Anu, Gu, Yan, Hsieh, Faye, Huang, Xin, H. Lee, Josie, Metz, Daniela, Middleton, Scot, Mohn, Deanna, Morgenstern, Kurt, J. Morrison, Michael, M. Novak, Perry, Oliveira-dos-Santos, Antonio, Powers, David, Rose, Paul, Schneider, Stephen, Sell, Stephanie, Tudor, Yanyan, M. Turci, Susan, A. Welcher, Andrew, D. White, Ryan, Zack, Debra, Zhao, Huilin, Zhu, Li, Zhu, Xiaotian, Ghiron, Chiara, Amouzegh, Patricia, Ermann, Monika, Jenkins, James, Johnston, David, Napier, Spencer, Power, Eoin |
| Zdroj: |
Journal of Medicinal Chemistry; August 2006, Vol. 49 Issue: 16 p4981-4991, 11p |
| Abstrakt: |
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure−activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation. |
| Databáze: |
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