Renin inhibitors for the treatment of hypertension: Design and optimization of a novel series of spirocyclic piperidines

The discovery and SAR of a novel series of spirocyclic renin inhibitors are described herein. It was found that by restricting the northern aromatic plate to the bioactive conformation through spirocyclization, increase in renin potency and decrease in hERG affinity could both be realized. When early members of this series were found to be potent time-dependent CYP3A4 inhibitors, two distinct strategies to address this liability were explored and this effort culminated in the identification of compound 31 as an optimized renin inhibitor.

Graphical abstractBy restricting the starting scaffold to its bioactive conformation in the renin enzyme, concomitant improvements in both renin potency and off-target profile (i.e., hERG and CYP) were realized.Figure optionsDownload full-size imageDownload as PowerPoint slide