Identification of 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivatives as potent and orally bioavailable STAT6 inhibitors.
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.
Nagashima
Shinya
S
Drug Discovery Research, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. shinya.nagashima@jp.astellas.com
Nagata
Hiroshi
H
Iwata
Masahiro
M
Yokota
Masaki
M
Moritomo
Hiroyuki
H
Orita
Masaya
M
Kuromitsu
Sadao
S
Koakutsu
Akiko
A
Ohga
Keiko
K
Takeuchi
Makoto
M
Ohta
Mitsuaki
M
Tsukamoto
Shin-ichi
S
D000284:Administration, Oral; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D051379:Mice; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009025:Morpholines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
C530490:4-benzylamino-2-((4-morpholin-4-ylphenyl)amino)pyrimidine-5-carboxamide; D009025:Morpholines; D011743:Pyrimidines; D050800:STAT6 Transcription Factor