Microwave-assisted synthesis of a pyrazolyl ketone library for evaluation as p38 MAPK inhibitors in Werner syndrome cells.

BACKGROUND: The pyrazolyl ketone motif of RO3201195, which exhibits good oral bioavailability and high selectivity for p38 MAPK over other kinases, is a key pharmacophore that could find application in the treatment of Werner syndrome. RESULTS AND DISCUSSION: Microwave irradiation promotes Knoevenagel condensation of a ß-ketonitrile and formamidine, to give ß-aminovinyl ketones, and their subsequent cyclocondensation with a subset of hydrazines to provide rapid access to a 24-membered library of pyrazolyl ketones. The library was evaluated in human hTERT-immortalized HCA2 dermal cells and Werner syndrome cells. CONCLUSION: Four compounds display comparable, if not slightly improved, potency over RO3201195.