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PDBsum entry 1d7x
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Design, Synthesis, And biological evaluation of matrix metalloproteinase inhibitors derived from a modified proline scaffold.
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Authors
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M.Cheng,
B.De,
N.G.Almstead,
S.Pikul,
M.E.Dowty,
C.R.Dietsch,
C.M.Dunaway,
F.Gu,
L.C.Hsieh,
M.J.Janusz,
Y.O.Taiwo,
M.G.Natchus,
T.Hudlicky,
M.Mandel.
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Ref.
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J Med Chem, 1999,
42,
5426-5436.
[DOI no: ]
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PubMed id
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Abstract
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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.
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