Cyclophilin D inhibitors that prevent opening of themitochondrialpermeability transition pore (MPTP) are potential treatments for arange of acute and chronic diseases, including acute pancreatitis.Here, we report that replacement of carbon with nitrogen in the pyrrolidineheadgroup of a series of cyclophilin D inhibitors gives a dramaticenhancement in binding affinity (>40 fold), and prolyl isomeraseinhibition(PPIase) activity (>200 fold), which is ascribed to a preorganizationof the pyrazolidine amide headgroup. This evidence concerns the gene PPIF and acute pancreatitis.