Renin Inhibitors. I. Synthesis and Structure-Activity Relationships of Transition-State Inhibitors Containing Homostatine Analogues at the Scissile Bond

The synthesis and structure-activity relationships of transition-state renin inhibitors containing the homostatine analogues at the scissile bond are described. These inhibitors incorporate the amino acid side chains corresponding to positions 7-12 (P_4-P_2') of angiotensinogen. Ethyl, 2-hydroxyethyl and 3-hydroxypropyl groups at position 2 of the homostatine analogues (P_1') are more effective for increasing potency than the isopropyl group. A combination of residues at P_1,P_3 and P_4 is important for potency and this result auggests that S_1,S_3 and S_4 form a huge hydrophobic core together in renin.