Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors.
Nagashima S, Yokota M, Nakai E, Kuromitsu S, Ohga K, Takeuchi M, Tsukamoto S, Ohta M.
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.