Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase

Jennifer A. Maier, Todd A. Brugel, Mark Sabat, Adam Golebiowski, Matthew J. Laufersweiler, John C. VanRens, Corey R. Hopkins, Biswanath De, Lily C. Hsieh, Kimberly K. Brown, Vijayasurian Easwaran, Michael J. Janusz

Research output: Contribution to journalArticle

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Abstract

A new class of lymphocyte specific tyrosine kinase (lck) inhibitors based on an N-4,6-pyrimidine-N-alkyl-N′-phenyl urea scaffold is described. Many of these compounds showed low-nanomolar inhibition of lck kinase activity as well as IL-2 synthesis from Jurkat cells. One of these analogs, 7i, was shown to be orally efficacious by in vivo testing in a rat adjuvant-induced arthritis study.

Original languageEnglish (US)
Pages (from-to)3646-3650
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume16
Issue number14
DOIs
StatePublished - Jul 15 2006

Fingerprint

Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
Experimental Arthritis
Jurkat Cells
Lymphocytes
Scaffolds
Protein-Tyrosine Kinases
Interleukin-2
Rats
Testing
pyrimidine
N-phenylurea

Keywords

  • IL-2 cytokine
  • Lck kinase
  • Rheumatoid arthritis
  • Trisubstituted ureas

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Maier, J. A., Brugel, T. A., Sabat, M., Golebiowski, A., Laufersweiler, M. J., VanRens, J. C., ... Janusz, M. J. (2006). Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase. Bioorganic and Medicinal Chemistry Letters, 16(14), 3646-3650. https://doi.org/10.1016/j.bmcl.2006.04.072

Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase. / Maier, Jennifer A.; Brugel, Todd A.; Sabat, Mark; Golebiowski, Adam; Laufersweiler, Matthew J.; VanRens, John C.; Hopkins, Corey R.; De, Biswanath; Hsieh, Lily C.; Brown, Kimberly K.; Easwaran, Vijayasurian; Janusz, Michael J.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 16, No. 14, 15.07.2006, p. 3646-3650.

Research output: Contribution to journalArticle

Maier, JA, Brugel, TA, Sabat, M, Golebiowski, A, Laufersweiler, MJ, VanRens, JC, Hopkins, CR, De, B, Hsieh, LC, Brown, KK, Easwaran, V & Janusz, MJ 2006, 'Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase', Bioorganic and Medicinal Chemistry Letters, vol. 16, no. 14, pp. 3646-3650. https://doi.org/10.1016/j.bmcl.2006.04.072
Maier, Jennifer A. ; Brugel, Todd A. ; Sabat, Mark ; Golebiowski, Adam ; Laufersweiler, Matthew J. ; VanRens, John C. ; Hopkins, Corey R. ; De, Biswanath ; Hsieh, Lily C. ; Brown, Kimberly K. ; Easwaran, Vijayasurian ; Janusz, Michael J. / Development of N-4,6-pyrimidine-N-alkyl-N′-phenyl ureas as orally active inhibitors of lymphocyte specific tyrosine kinase. In: Bioorganic and Medicinal Chemistry Letters. 2006 ; Vol. 16, No. 14. pp. 3646-3650.
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