2ofu Citations

Novel 2-aminopyrimidine carbamates as potent and orally active inhibitors of Lck: synthesis, SAR, and in vivo antiinflammatory activity.

Abstract

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.

Articles - 2ofu mentioned but not cited (1)

  1. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL. Sci Signal 8 rs13 (2015)


Reviews citing this publication (2)

  1. Update on lymphocyte specific kinase inhibitors: a patent survey. Martin MW, Machacek MR. Expert Opin Ther Pat 20 1573-1593 (2010)
  2. Update on lymphocyte specific kinase inhibitors: a patent survey. Martin MW, Machacek MR. Expert Opin Ther Pat 20 1573-1593 (2010)

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  4. Targeting kinases for the treatment of inflammatory diseases. Müller S, Knapp S. Expert Opin Drug Discov 5 867-881 (2010)
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  10. N-(3-(phenylcarbamoyl)arylpyrimidine)-5-carboxamides as potent and selective inhibitors of Lck: structure, synthesis and SAR. Deak HL, Newcomb JR, Nunes JJ, Boucher C, Cheng AC, DiMauro EF, Epstein LF, Gallant P, Hodous BL, Huang X, Lee JH, Patel VF, Schneider S, Turci SM, Zhu X. Bioorg. Med. Chem. Lett. 18 1172-1176 (2008)
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  13. Virtual screening of specific insulin-like growth factor 1 receptor (IGF1R) inhibitors from the National Cancer Institute (NCI) molecular database. Fan C, Huang YX, Bao YL, Sun LG, Wu Y, Yu CL, Zhang Y, Song ZB, Zheng LH, Sun Y, Wang GN, Li YX. Int J Mol Sci 13 17185-17209 (2012)
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