Disubstituted pyrimidines as Lck inhibitors

Bioorganic and Medicinal Chemistry Letters

Volumn 19, Issue 18, 2009, Pages 5440-5443

  Hunt, Julianne A ^a   Beresis, Richard T ^a   Goulet, Joung L ^a   Holmes, Mark A ^a   Hong, Xinfang J ^a   Kovacs, Ernest ^a   Mills, Sander G ^a   Ruzek, Rowena D ^a   Wong, Frederick ^a   Hermes, Jeffrey D ^a   Park, Young Whan ^a   Salowe, Scott P ^a   Sonatore, Lisa M ^a   Wu, Lin ^a   Woods, Andrea ^a   Zaller, Dennis M ^a   Sinclair, Peter J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Autoimmune disease; Lck; Protein tyrosine kinase; Pyrimidine; Rheumatoid arthritis; Src

Indexed keywords

4 BENZIMIDAZOLYL N PIPERAZINETHYLPYRIMIDIN 2 AMINE DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; INTERLEUKIN 2; PIPERAZINE DERIVATIVE; PROTEIN KINASE INHIBITOR; PROTEIN KINASE LCK; PROTEIN KINASE LCK INHIBITOR; UNCLASSIFIED DRUG;

ARTICLE; CYTOKINE RELEASE; DRUG SYNTHESIS; ENZYME INHIBITION; IC 50; REACTION ANALYSIS; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

INHIBITORY CONCENTRATION 50; INTERLEUKIN-2; LYMPHOCYTE SPECIFIC PROTEIN TYROSINE KINASE P56(LCK); MOLECULAR STRUCTURE; PROTEIN KINASE INHIBITORS; PYRIMIDINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68949122712     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2009.07.102     Document Type: Article

References (12)

1. Alberola-Ila J., Takaki S., Kerner J.D., and Perlmutter R.M. Annu. Rev. Immunol. 15 (1997) 125
2. Bolen J.B., and Brugge J.S. Annu. Rev. Immunol. 15 (1997) 371
3. Chan A.C., Desai D.M., and Weiss A. Annu. Rev. Immunol. 12 (1994) 555
4. Martin M.W., Newcomb J., Nunes J.J., Boucher C., Chai L., Epstein L.F., Faust T., Flores S., Gallant P., Gore A., Gu Y., Hsieh F., Huang X., Kim J.L., Middleton S., Morgenstern K., Oliveira-dos-Santos A., Patel V.F., Poers D., Rose P., Tudor Y., Turci S.M., Welcher A.A., Zack D., Zhao H., Zhu L., Zhu X., Ghiron C., Ermann M., Johnston D., and Saluste C.-G.P. J. Med. Chem. 51 (2008) 1637 and references therein
5. Burchat A., Borhani Q.W., Caldewood D.J., Hirst G.C., Li B., and Stachlewitz R.F. Bioorg. Med. Chem. Lett. 16 (2006) 118 and references therein
6. Maier J.A., Brugel T.A., Sabat M., Golebiowski A., Laufersweiler M.J., VanRens J.C., Hopkins C.R., De B., Hsieh L.C., Brown K.K., Easwaran V., and Janusz M.J. Bioorg. Med. Chem. Lett. 16 (2006) 3646 and references therein
7. Chen P., Doweyko A.M., Norris D., Gu H.H., Spergel S.H., Das J., Moquin R.V., Lin J., Wityak J., Iwanowicz E.J., McIntyre K.W., Shuster D.J., Behnia K., Ching S., de Fex H.F., Pang S., Pitt S., Shen D.R., Thrall S., Stanley P., Kocy O.R., Witmer M.R., Kanner S.B., Schieven G.L., and Barrish J.C. J. Med. Chem. 47 (2004) 4517 and references therein
8. For a recent report of disubstituted pyrimidines as Lck inhibitors, see Ref. [2a].
9. Park Y.-W., Cummings R.T., Wu L., Zheng S., Cameron P.M., Woods A., Zaller D.M., Marcy A.I., and Hermes J.D. Anal. Biochem. 269 (1999) 94
10. Hunt, J. A., et al. Unpublished data.
11. To evaluate inhibition of downstream signaling events, compounds were assayed for their ability to block antigen-stimulated IL-2 release in stable Jurkat cell transformants expressing a TCR specific for the MART-1 antigen (Cole, D. J.; Weil, D. P.; Shilyansky, J.; Custer, M.; Kawakami, Y.; Rosenberg, S. A.; Nishimura, M. I. Cancer Res., 1995, 55, 748).
12. See Supplementary data for synthetic schemes and additional data.