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

doi: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

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 journal › Article › peer-review

20 Scopus citations

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 language	English (US)
Pages (from-to)	3646-3650
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	16
Issue number	14
DOIs	https://doi.org/10.1016/j.bmcl.2006.04.072
State	Published - Jul 15 2006
Externally published	Yes

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

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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., & 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

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

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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.",

keywords = "IL-2 cytokine, Lck kinase, Rheumatoid arthritis, Trisubstituted ureas",

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doi = "10.1016/j.bmcl.2006.04.072",

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AU - Maier, Jennifer A.

AU - Brugel, Todd A.

AU - Sabat, Mark

AU - Golebiowski, Adam

AU - Laufersweiler, Matthew J.

AU - VanRens, John C.

AU - Hopkins, Corey R.

AU - De, Biswanath

AU - Hsieh, Lily C.

AU - Brown, Kimberly K.

AU - Easwaran, Vijayasurian

AU - Janusz, Michael J.

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AB - 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.

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KW - Lck kinase

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KW - Trisubstituted ureas

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

Abstract

Keywords

ASJC Scopus subject areas

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