title: Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors.
abstract: The STAT6 (signal transducers and activators of transcription 6) protein is activated by interleukin (IL)-4 and IL-13, and plays an important role in T-helper cell 2 (Th2) differentiation. STAT6 might therefore be an excellent therapeutic target for various allergic conditions, including asthma and atopic diseases. We synthesized a series of 2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 4-(benzylamino)-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide (2t, AS1517499) showed potent STAT6 inhibition with an IC(50) value of 21 nM, and also inhibited IL-4-induced Th2 differentiation of mouse spleen T cells with an IC(50) value of 2.3 nM and without influencing T-helper cell 1 (Th1) differentiation induced by IL-12.
authors.affiliation: Institute for Drug Discovery Research, Astellas Pharm Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka 532-8514, Japan. shinya.nagashima@jp.astellas.com
authors.forename: Shinya
authors.initials: S
authors.lastname: Nagashima
authors.forename: Masaki
authors.initials: M
authors.lastname: Yokota
authors.forename: Ei-Ichi
authors.initials: E
authors.lastname: Nakai
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
authors.forename: Keiko
authors.initials: K
authors.lastname: Ohga
authors.forename: Makoto
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005021:Ethylamines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017930:Genes, Reporter; D006801:Humans; D007202:Indicators and Reagents; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007536:Isomerism; D008156:Luciferases / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D010957:Plasmids; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D050800:STAT6 Transcription Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects; D018418:Th2 Cells
chemical_list: C517829:2-((2-(4-hydroxyphenyl)-ethyl)amino)pyrimidine-5-carboxamide; D005021:Ethylamines; D007202:Indicators and Reagents; D011743:Pyrimidines; D050800:STAT6 Transcription Factor; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D008156:Luciferases