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

Article Details

Citation

Copy to clipboard

Cheng M, De B, Almstead NG, Pikul S, Dowty ME, Dietsch CR, Dunaway CM, Gu F, Hsieh LC, Janusz MJ, Taiwo YO, Natchus MG, Hudlicky T, Mandel M

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

J Med Chem. 1999 Dec 30;42(26):5426-36.

PubMed ID

10639284 [ View in PubMed

]

Abstract

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 sp(2) 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 sp(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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-Hydroxy 1n(4-Methoxyphenyl)Sulfonyl-4-(Z,E-N-Methoxyimino)Pyrrolidine-2r-Carboxamide	Stromelysin-1	IC 50 (nM)	19	N/A	N/A	Details