PREPARATION OF A NOVEL SERIES OF PHOSPHONATE NORSTATINE RENIN INHIBITORS

Replacement of the C-terminal isopropyl ester in the orally active norstatine renin inhibitor terlakiren (1) with dialkyl phosphonate groups provided a novel series of phosphorus norstatine inhibitors 2. Cyclic phosphonate 2f (IC50 = 0.6 nM) was prepared in an attempt to overcome apparent steric limitations of the phosphonate binding pocket and was found to be equipotent to ester 1. Like the ester norstatines, the phosphonate inhibitors preferred nonpolar P2 residues.