Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors

Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-10, Vol.17 (19), p.6926-6936
Main Authors: Nagashima, Shinya, Hondo, Takeshi, Nagata, Hiroshi, Ogiyama, Takashi, Maeda, Jun, Hoshii, Hiroaki, Kontani, Toru, Kuromitsu, Sadao, Ohga, Keiko, Orita, Masaya, Ohno, Kazuki, Moritomo, Ayako, Shiozuka, Koichi, Furutani, Masako, Takeuchi, Makoto, Ohta, Mitsuaki, Tsukamoto, Shin-ichi
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Asthma - drug therapy
Cytochrome P-450 CYP3A
Cytochrome P-450 CYP3A Inhibitors
Eosinophils - drug effects
Humans
Immunity
Mice
Pyrimidines - chemical synthesis
Pyrimidines - pharmacology
Pyrimidines - therapeutic use
Pyrroles - chemical synthesis
Pyrroles - pharmacology
Pyrroles - therapeutic use
STAT6 Transcription Factor - antagonists & inhibitors
Structure-Activity Relationship
Th2 Cells - drug effects
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Summary:Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in interleukin (IL)-4 signaling pathway and a key regulator of the type 2 helper T (Th2) cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases. Previously, we reported 4-aminopyrimidine-5-carboxamide derivatives as STAT6 inhibitors. To search for novel STAT6 inhibitors, we synthesized fused bicyclic pyrimidine derivatives and identified a 7H-pyrrolo[2,3-d]pyrimidine derivative as a STAT6 inhibitor. Optimization of the pyrrolopyrimidine derivatives led to identification of 2-[4-(4-{[7-(3,5-difluorobenzyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl]amino}phenyl)piperazin-1-yl]acetamide (24, AS1810722) which showed potent STAT6 inhibition and a good CYP3A4 inhibition profile. Compound 24 also inhibited in vitro Th2 differentiation without affecting type 1 helper T (Th1) cell differentiation and eosinophil infiltration in an antigen-induced mouse asthmatic model after oral administration.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.08.021