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 InhibitorsABSTRACT
Herein we describe a short total synthesis of (+)-spinoxazine B, which inhibits nitric oxide (NO) production in BV-2 microgrial cells. Spinoxazine B is the first example of a natural alkaloid containing an oxazinone-pyrrolidone nucleus, and it is expected to serve as a novel drug lead compound as well as a drug discovery scaffold.