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

Bioorg Med Chem Lett. 2006 Jul 15;16(14):3646-50. doi: 10.1016/j.bmcl.2006.04.072. Epub 2006 May 8.

Authors

Jennifer A Maier¹, 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

Affiliation

¹ Procter & Gamble Pharmaceuticals, Health Care Research Center, 8700 Mason-Montgomery Rd. Mason, OH 45040, USA.

PMID: 16682201
DOI: 10.1016/j.bmcl.2006.04.072

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.

MeSH terms

Administration, Oral
Animals
Arthritis, Experimental / drug therapy
Arthritis, Experimental / pathology
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / pharmacology
Enzyme Inhibitors / therapeutic use
Humans
Interleukin-2 / biosynthesis
Jurkat Cells
Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
Molecular Structure
Phenylurea Compounds / chemical synthesis*
Phenylurea Compounds / pharmacology
Pyrimidines / chemistry*
Rats

Substances

Enzyme Inhibitors
Interleukin-2
Phenylurea Compounds
Pyrimidines
Lymphocyte Specific Protein Tyrosine Kinase p56(lck)