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Bioorg Med Chem Lett ; 97: 129541, 2024 01 01.
Article in English | MEDLINE | ID: mdl-37952596

ABSTRACT

Matrix metalloproteinase-9 (MMP-9) is a secreted zinc-dependent endopeptidase that degrades the extracellular matrix and basement membrane of neurons, and then contributes to synaptic plasticity by remodeling the extracellular matrix. Inhibition of MMP-9 activity has therapeutic potential for neurodegenerative diseases such as fragile X syndrome. This paper reports the molecular design, synthesis, and in vitro studies of novel indole derivatives as inhibitors of proMMP-9 activation. High-throughput screening (HTS) of our internal compound library and subsequent merging of hit compounds 1 and 2 provided compound 4 as a bona-fide lead. X-ray structure-based design and subsequent lead optimization led to the discovery of compound 33, a highly potent and selective inhibitor of proMMP-9 activation.


Subject(s)
Enzyme Precursors , Matrix Metalloproteinase 9 , Matrix Metalloproteinase 9/metabolism , Enzyme Precursors/metabolism , Extracellular Matrix/metabolism , Indoles/pharmacology , Indoles/metabolism , Metalloendopeptidases/metabolism , Matrix Metalloproteinase Inhibitors
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