Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The da ta reveal a remarkable potency enhancement in those compounds that contain an sp(2) center at the C-4 carbon of the ring relative to similar, saturate d compounds. This effect was noted in compounds that contained a functional ized oxime moiety or an exomethylene at C-4, and the potencies were typical ly <10 nM for MMP-3 and <100 nM for MMP-1. Comparisons were then made again st compounds with similar functionality where the C-4 carbon was reduced to sp(3) hybridization and the effect was typically an order of magnitude los s in potency. A comparison of compounds 14 and 34 exemplifies this observat ion. An X-ray structure was obtained for a stromelysin-inhibitor complex wh ich provided insights into the SAR and selectivity trends observed within t he series. In vitro intestinal permeability data for many compounds was als o accumulated.