Carbamoylphosphonate MMP inhibitors. Part 4: The influence of chirality and geometrical isomerism on the potency and selectivity of inhibition

Matrix metalloproteinases (MMPs) are a family of over twenty zinc-dependent enzymes that hydrolyze connective tissue and are involved in a variety of diseases, which are associated with undesired tissue breakdown. Previously we described the synthesis of a series of achiral alkyl and cycloalkylcarbamoylphosphonic acids and their biological evaluation. Herein we report the effect of chirality and geometrical isomerism on the potency and selectivity of inhibition. The inhibitory potencies of pairs of enantiomeric and stereoisomeric alkyl and cycloalkylcarbamoylphosphonic acids were evaluated on recombinant MMP-1, MMP-2, MMP-3, MMP-8, and MMP-9 enzymes. The results show that the enantiomers and stereoisomers studied differ considerably in their inhibitory potencies and selectivities on the enzyme subtypes studied. Such a result is consistent with the assumption that the carbamoylphosphonates interact with a chiral environment such as an enzyme.