Signal transducers and activators of transcription 6 (STAT6) is an important transcription factor in IL-4 signaling pathway. STAT6 is also a key regulator of the Th2 cell immune response. Therefore, STAT6 may be an excellent therapeutic target for allergic conditions, including asthma and atopic diseases.
To search for novel STAT6 inhibitors, researchers synthesized fused bicyclic pyrimidine derivatives and evaluated their activities. Among these compounds, AS1810722 shows potent STAT6 inhibitory activity and a good CYP3A4 profile. AS1810722 shows potent STAT6 inhibition and a good CYP3A4 inhibition profile. STAT6 also plays a critical role in Th2 lung inflammatory responses including clearance of parasitic infections and in the pathogenesis of asthma.
AS1810722 inhibits in vitro Th2 differentiation with an IC50 of 2.4 nM. AS1810722 does not affect Th1 cell differentiation. Moreover, AS1810722 also suppresses eosinophil infiltration in an antigen-induced mouse asthmatic model after oral administration. AS1810722 inhibits STAT6 activation with an IC50 value of 1.9 nM and shows a good profile of CYP3A4 inhibition. AS1810722 is a novel potent and orally active STAT6 inhibitor that is useful for the treatment of allergic diseases such as asthma and atopic diseases. Besides, AS1810722 is the most promising compound from the perspectives of STAT6 inhibition and the CYP3A4 profile. Furthermore, AS1810722 inhibits the production of IL-4 with an IC50 of 2.4 nM, but shows no effect on production of IFN-γ. AS1810722 (0.03–0.3 mg/kg) suppresses eosinophil infiltration in the lung in a dose-dependent manner after oral administration
All in all, AS1810722 is a potent and orally active STAT6 inhibitor, may be useful for the treatment of allergic diseases such as asthma and atopic diseases.
Shinya Nagashima, et al. Novel 7H-pyrrolo[2,3-d]pyrimidine derivatives as potent and orally active STAT6 inhibitors. Bioorg Med Chem. 2009 Oct 1;17(19):6926-36.