2ofu Citations

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


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)
  5. Discovery and preliminary structure-activity relationship studies of novel benzotriazine based compounds as Src inhibitors. Noronha G, Barrett K, Cao J, Dneprovskaia E, Fine R, Gong X, Gritzen C, Hood J, Kang X, Klebansky B, Li G, Liao W, Lohse D, Mak CC, McPherson A, Palanki MS, Pathak VP, Renick J, Soll R, Splittgerber U, Wrasidlo W, Zeng B, Zhao N, Zhou Y. Bioorg. Med. Chem. Lett. 16 5546-5550 (2006)
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  7. Discovery of novel 2,3-diarylfuro[2,3-b]pyridin-4-amines as potent and selective inhibitors of Lck: synthesis, SAR, and pharmacokinetic properties. Martin MW, Newcomb J, Nunes JJ, Bemis JE, McGowan DC, White RD, Buchanan JL, DiMauro EF, Boucher C, Faust T, Hsieh F, Huang X, Lee JH, Schneider S, Turci SM, Zhu X. Bioorg. Med. Chem. Lett. 17 2299-2304 (2007)
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  9. Development of a time-resolved fluorescence resonance energy transfer assay for cyclin-dependent kinase 4 and identification of its ATP-noncompetitive inhibitors. Lo MC, Ngo R, Dai K, Li C, Liang L, Lee J, Emkey R, Eksterowicz J, Ventura M, Young SW, Xiao SH. Anal. Biochem. 421 368-377 (2012)
  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)
  11. A Discovery Strategy for Selective Inhibitors of c-Src in Complex with the Focal Adhesion Kinase SH3/SH2-binding Region. Moroco JA, Baumgartner MP, Rust HL, Choi HG, Hur W, Gray NS, Camacho CJ, Smithgall TE. Chem Biol Drug Des 86 144-155 (2015)
  12. Identification of Aminoimidazole and Aminothiazole Derivatives as Src Family Kinase Inhibitors. Francini CM, Fallacara AL, Artusi R, Mennuni L, Calgani A, Angelucci A, Schenone S, Botta M. ChemMedChem 10 2027-2041 (2015)
  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)
  14. The use of salt-inducible kinase inhibitors to treat autoimmune and inflammatory diseases: evaluation of WO2013136070. Norman P. Expert Opin Ther Pat 24 943-946 (2014)