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.
Shinya Nagashima  1 ,  Hiroshi Nagata ,  Masahiro Iwata ,  Masaki Yokota ,  Hiroyuki Moritomo ,  Masaya Orita ,  Sadao Kuromitsu ,  Akiko Koakutsu ,  Keiko Ohga ,  Makoto Takeuchi ,  Mitsuaki Ohta ,  Shin-ichi Tsukamoto
Affiliations
  • 1. Drug Discovery Research, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. [email protected]
PMID: 18534856 DOI: 10.1016/j.bmc.2008.05.031
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.

Products