Ketopiperazine-based renin inhibitors: Optimization of the “C” ring

A series of ketopiperazine-based renin inhibitors designed to interact in the S3 sub-pocket of the renin protein were evaluated for renin inhibitory activity. The investigation revealed that linear and sterically small side chain substituents are preferred in the S3 sub-pocket for optimal renin inhibition. Polar groups in the S3 sub-pocket were not well tolerated and caused a reduction in renin inhibitory activity. Further, compounds with c log P's ⩽ 3 demonstrated a dramatic reduction in CYP3A4 inhibitory activity.