256488-00-3Relevant articles and documents
Design, synthesis, and biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold
Cheng, Menyan,De, Biswanath,Almstead, Neil G.,Pikul, Stanislaw,Dowty, Martin E.,Dietsch, Charles R.,Dunaway, C. Michelle,Gu, Fei,Hsieh, Lily C.,Janusz, Michael J.,Taiwo, Yetunde O.,Natchus, Michael G.,Hudlicky, Tomas,Mandel, Martin
, p. 5426 - 5436 (2007/10/03)
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 3 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.
