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-ca rboxamide (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.

中文翻译：

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鉴定4-苄氨基-2-[（（4-吗啉-4-基苯基）氨基]嘧啶-5-羧酰胺衍生物作为有效的和口服可生物利用的STAT6抑制剂。

信号转导和转录激活因子6（STAT6）是2型辅助T（Th2）细胞免疫应答的关键调节剂，是过敏性疾病（例如哮喘和特应性疾病）的潜在治疗靶标。为了寻找有效的和口服可生物利用的STAT6抑制剂，我们合成了一系列的4-苄基氨基嘧啶-5-羧酰胺衍生物，并评估了它们对STAT6的抑制活性。在这些化合物中，2-[（（4-吗啉-4-基苯基）氨基] -4-[（2,3,6-三氟苄基）氨基]嘧啶-5-邻甲酰胺（25y，YM-341619，AS1617612）显示有效STAT6抑制，其IC（50）为0.70nM，并且还抑制了白介素（IL）-4诱导的小鼠脾T细胞中Th2的分化，IC（50）为0.28 nM，而不会影响1型辅助性T（Th1）细胞的分化由IL-12诱导。此外，