Identification of 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivatives as potent and orally bioavailable STAT6 inhibitors

Bioorg Med Chem. 2008 Jul 1;16(13):6509-21. doi: 10.1016/j.bmc.2008.05.031. Epub 2008 May 17.

Abstract

Signal transducers and activators of transcription 6 (STAT6) is a key regulator of the type 2 helper T (Th2) cell immune response and a potential therapeutic target for allergic diseases such as asthma and atopic diseases. To search for potent and orally bioavailable STAT6 inhibitors, we synthesized a series of 4-benzylaminopyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 2-[(4-morpholin-4-ylphenyl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide (25y, YM-341619, AS1617612) showed potent STAT6 inhibition with an IC(50) of 0.70nM, and also inhibited Th2 differentiation in mouse spleen T cells induced by interleukin (IL)-4 with an IC(50) of 0.28 nM without affecting type 1 helper T (Th1) cell differentiation induced by IL-12. In addition, compound 25y showed an oral bioavailability of 25% in mouse.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Chemical Phenomena
  • Chemistry, Physical
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Morpholines / administration & dosage*
  • Morpholines / chemistry
  • Morpholines / pharmacokinetics
  • Morpholines / pharmacology*
  • Pyrimidines / administration & dosage*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • STAT6 Transcription Factor / antagonists & inhibitors*
  • STAT6 Transcription Factor / metabolism
  • Structure-Activity Relationship
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism

Substances

  • 4-benzylamino-2-((4-morpholin-4-ylphenyl)amino)pyrimidine-5-carboxamide
  • Morpholines
  • Pyrimidines
  • STAT6 Transcription Factor