Fluoro ketone containing peptides as inhibitors of human renin

The pentapeptide BOC-Phe-Phe-difluorostatone-Leu-Phe-NH2 has been prepared and found to be a potent inhibitor of human renin. This compound contains a difluoromethylene ketone group that exists predominantly in the hydrated form in water. The difluorostatone-containing peptide is 7-fold and 22-fold more potent than the analogous statine- and statone-containing peptides, respectively. Structure/activity analysis of the most potent inhibitor was carried out by replacing some of the peptide bonds with trans-alkenes. In all cases, a dramatic loss in binding to renin was observed. A number of statine-containing inhibitors of renin have been reported and this work suggests that the replacement of statine with difluorostatone will yield more potent compounds.