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

• Published in: Bioorganic & medicinal chemistry Vol. 16; no. 13; pp. 6509 - 6521
• Main Authors: Nagashima, Shinya, Nagata, Hiroshi, Iwata, Masahiro, Yokota, Masaki, Moritomo, Hiroyuki, Orita, Masaya, Kuromitsu, Sadao, Koakutsu, Akiko, Ohga, Keiko, Takeuchi, Makoto, Ohta, Mitsuaki, Tsukamoto, Shin-ichi
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.07.2008; Elsevier Science
• Subjects: Administration, Oral; Allergic disease; Animals; Biological and medical sciences; Cell Differentiation - drug effects; Cells, Cultured; Chemical Phenomena; Chemistry, Physical; Immunomodulators; Interleukin-4; Medical sciences; Mice; Mice, Inbred C57BL; Molecular Structure; Morpholines - administration & dosage; Morpholines - chemistry; Morpholines - pharmacokinetics; Morpholines - pharmacology; Pharmacology. Drug treatments; Pyrimidines - administration & dosage; Pyrimidines - chemistry; Pyrimidines - pharmacokinetics; Pyrimidines - pharmacology; Signal transducers and activators of transcription 6; STAT6 Transcription Factor - antagonists & inhibitors; STAT6 Transcription Factor - metabolism; Structure-Activity Relationship; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Th2 differentiation; Th2 differentiation; Interleukin-4; Signal transducers and activators of transcription 6; Allergic disease; Nitrogen heterocycle; Morpholine derivatives; Interleukin 4; Transcription factor STAT6; Six membered ring; T-Lymphocyte; Th2 lymphocyte; Inhibition; Oxygen nitrogen heterocycle; Spleen; Rodentia; Oral administration; Bioavailability; Cell differentiation; Immunomodulator; Vertebrata; Mammalia; Mouse; Animal; Carboxamide; Pyrimidine derivatives; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2008.05.031

The novel 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivative 25y (YM-341619, AS1617612) potently inhibited STAT6 activation and Th2 differentiation with IC 50 values of 0.70 and 0.28 nM, respectively, and showed an oral bioavailability of 25% in mouse. 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 0.70 nM, 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.