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1.
Bioorg Med Chem Lett ; 97: 129541, 2024 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-37952596

RESUMO

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.


Assuntos
Precursores Enzimáticos , Metaloproteinase 9 da Matriz , Metaloproteinase 9 da Matriz/metabolismo , Precursores Enzimáticos/metabolismo , Matriz Extracelular/metabolismo , Indóis/farmacologia , Indóis/metabolismo , Metaloendopeptidases/metabolismo , Inibidores de Metaloproteinases de Matriz
2.
Chem Pharm Bull (Tokyo) ; 66(12): 1196-1198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30504633

RESUMO

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.


Assuntos
Oxazinas/síntese química , Animais , Linhagem Celular Transformada , Camundongos , Conformação Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Oxazinas/química , Oxazinas/farmacologia , Estereoisomerismo
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