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A novel series of hydrozamate-based inhibitors of matrix metalloproteinases containing benzimidazole and imidazole heterocyles as amide bond isosteres have been prepared. Potent inhibition (in the low nanomolar range) and selectivity (> 100-fold) can be attained with inhibitors containing only one amide bond. X-ray crystal structures of matrilysin (MMP-7) with two different inhibitors bound confirm that imidazole is an excellent amide bond isostere.

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.

Conformationally-constrained macrocyclic peptide-based hydroxyethylamines, with 17- to 19-membered ring systems, have been designed and synthesized as HIV protease inhibitors. Structure-activity relationships were consistent with molecular modeling studies, and certain cyclic inhibitors were developed with HIV protease IC50 values of ∼1 nM, and antiviral activities (HIV-1/RF infected MT-2 cells) of EC50 4–8 nM.