Rapid synthesis of VX-745: p38 MAP kinase inhibition in Werner syndrome cells

The p38 mitogen-activated protein kinase inhibitor VX-745 is prepared rapidly and efficiently in a four-step sequence using a combination of conductive heating and microwave-mediated steps. Its inhibitory activity was confirmed in hTERT immortalized HCA2 and WS dermal fibroblasts at 0.5–1.0 μM concentration by ELISA and immunoblot assay, and displays excellent kinase selectivity over the related stress-activated kinase JNK.

Graphical abstractA novel and efficient synthesis of VX-745 using primarily microwave dielectric heating is reported. Inhibition of p38α MAP kinase by VX-745 in Werner syndrome cells shows very high selectivity over the related JNK kinase.Figure optionsDownload full-size imageDownload as PowerPoint slide