Benzyl ether structure–activity relationships in a series of ketopiperazine-based renin inhibitors

Inhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(π + σ) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.

Graphical abstractInhibition of renin enzymatic activity by a series of ketopiperazine-based compounds containing a C6 benzyloxymethyl substituent correlated with a +(π + σ) effect. A 3-pyridinyloxymethyl substituent was also found to be equipotent as higher molecular weight analogs, and exhibited decreased CYP3A4 inhibition levels and improved pharmacokinetic properties.Figure optionsDownload full-size imageDownload as PowerPoint slide