Design, synthesis, activity, and structure of a novel class of matrix metalloproteinase inhibitors containing a heterocyclic P 2′-P 3′ amide bond isostere

Abstract

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.