Novel 2-Aminopyrimidine Carbamates as Potent and Orally Active Inhibitors of Lck: Synthesis, SAR, and in Vivo Antiinflammatory Activity
journal contributionposted on 10.08.2006 by Matthew W. Martin, John Newcomb, Joseph J. Nunes, David C. McGowan, David M. Armistead, Christina Boucher, John L. Buchanan, William Buckner, Lilly Chai, Daniel Elbaum, Linda F. Epstein, Theodore Faust, Shaun Flynn, Paul Gallant, Anu Gore, Yan Gu, Faye Hsieh, Xin Huang, Josie H. Lee, Daniela Metz, Scot Middleton, Deanna Mohn, Kurt Morgenstern, Michael J. Morrison, Perry M. Novak, Antonio Oliveira-dos-Santos, David Powers, Paul Rose, Stephen Schneider, Stephanie Sell, Yanyan Tudor, Susan M. Turci, Andrew A. Welcher, Ryan D. White, Debra Zack, Huilin Zhao, Li Zhu, Xiaotian Zhu, Chiara Ghiron, Patricia Amouzegh, Monika Ermann, James Jenkins, David Johnston, Spencer Napier, Eoin Power
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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.