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 β-ketonitrile and formamidine, to give β-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.