Patent Evaluation Cardiovascular & Renal: Phosphinic acid derivatives as endothelin converting enzyme inhibitors

Abstract

Endothelin-1 is the most potent peptide vasoconstrictor known and has been implicated in the pathogenesis of various cardiovascular, renal and central nervous system diseases. Since the final step of biosynthesis of this vasoactive peptide is catalysed by endothelin converting enzyme, inhibitors of this enzyme are expected to have beneficial effects for diseases associated with an overproduction of endothelin-1. This patent application discloses a series of phosphinic acid derivatives as endothelin converting enzyme inhibitors. The most potent compound inhibits endothelin converting enzyme activity in vitro with an IC₅₀ of 27 nM. In addition, compound 1 is shown to be orally active in an ex vivo assay.