Microwave-assisted synthesis of 5-aminopyrazol-4-yl ketones and the p38MAPK inhibitor RO3201195 for study in Werner syndrome cells

5-Aminopyrazol-4-yl ketones are prepared rapidly and efficiently using microwave dielectric heating from β-ketonitriles by treatment with N,N′-diphenylformamidine followed by heterocyclocondensation by irradiation with a hydrazine. The inhibitory activity of RO3201195 prepared by this methodology was confirmed in hTERT-immortalized HCA2 and WS dermal fibroblasts at 200 nM concentration, both by ELISA and immunoblot assay, and displays excellent kinase selectivity for p38α MAPK over the related stress-activated kinase JNK.

Graphical abstract5-Aminopyrazol-4-yl ketones can be prepared rapidly and efficiently using microwave heating for elaboration to the p38α MAP kinase inhibitor, RO3201195, which shows very high selectivity in Werner syndrome cells over JNK kinase.Figure optionsDownload full-size imageDownload as PowerPoint slide