Synthesis and in vivo activity of MK2 and MK2 substrate-selective p38αMAPK inhibitors in Werner syndrome cells

A benzopyranopyridine inhibitor of mitogen-activated protein kinase-activated protein kinase 2 (MK2) is prepared rapidly and efficiently in one step using microwave dielectric heating, whereas a substrate-selective p38 MAPK inhibitor was prepared using conventional heating techniques. The former had MK2 inhibitory activity above 2.5 mu M concentration, whereas the latter showed no MK2 inhibition at 10 mu M. However, rather than rescuing the reduced cellular growth rate and aged morphology of hTERT-immortalised WS dermal fibroblasts, both induce a state resembling stress-induced cellular senescence, suggesting that these inhibitors may have limited therapeutic use. (c) 2007 Elsevier Ltd. All rights reserved.