Synthesis and activity of conformationally-constrained macrocyclic norstatine-based inhibitors of HIV protease

Two diastereomers of a macrocyclic hydroxyamide (norstatine-based) peptide, having an 18-membered ring system, have been synthesized as HIV protease inhibitors. The (R)-diastereomer (IC50 19 nM) was 17-fold weaker than an acyclic analog, but had comparable or better antiviral activity, suggesting improved cell penetration properties and/or resistance to cellular enzymes for the macrocyclic inhibitor.