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

Article abstract of DOI:10.1021/jm9904699

The synthesis and structure-activity relationship (SAR) studies of a series of proline-based matrix metalloproteinase inhibitors are described. The data reveal a remarkable potency enhancement in those compounds that contain an sp² center at the C-4 carbon of the ring relative to similar, saturated compounds. This effect was noted in compounds that contained a functionalized oxime moiety or an exomethylene at C-4, and the potencies were typically < 10 nM for MMP-3 and < 100 nM for MMP- 1. Comparisons were then made against compounds with similar functionality where the C-4 carbon was reduced to sp³ hybridization and the effect was typically an order of magnitude loss in potency. A comparison of compounds 14 and 34 exemplifies this observation. An X-ray structure was obtained for a stromelysin-inhibitor complex which provided insights into the SAR and selectivity trends observed within the series. In vitro intestinal permeability data for many compounds was also accumulated.