Design and synthesis of P2-P1'-linked macrocyclic human renin inhibitors

Article abstract of DOI:10.1021/jm00113a005

Using a computer model of the active site of human renin developed at Merck, we designed a series of novel P₂-P₁'-linked, macrocyclic renin inhibitors 3-10. These unique inhibitors incorporate a transition-state isostere within a 13- or 14-membered ring. The three most active compounds in this family were 13-membered-ring glutamine-derived inhibitor 3, 14-membered-ring diaminopropionic acid derived inhibitor 6, and 13-membered-ring diol 9 (IC₅₀ 0.61, 0.59, 0.65 μM, respectively). Modification of inhibitor 3 at P₄ led to 56 nM macrocyclic renin inhibitor 39. This study shows the viability of renin inhibitor designs which incorporate a scissile-bond replacement within a macrocycle.