Bioorganic & medicinal chemistry letters · 2023
Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation.
СтатьяНазвание и аннотация: Перевод в очереди
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Nishikawa-Shimono Rie, Kuwabara Motoi, Fujisaki Sho, Matsuda Daisuke, Endo Mayumi, Kamitani Masafumi, Futamura Aya, Nomura Yusaku, Yamaguchi-Sasaki Toru, Yabuuchi Tetsuya, Yamaguchi Chitose, Tanaka-Yamamoto Nozomi, Satake Shunya, Abe-Sato Kumi, Funayama Kosuke, Sakata Mayumi, Takahashi Shinji, Hirano Koga, Fukunaga Takuya, Uozumi Yoriko, Kato Sayaka, Tamura Yunoshin, Nakamori Tomoaki, Mima Masashi, Mishima-Tsumagari Chiemi, Nozawa Dai, Imai Yudai, Asami Taiji
Аннотация
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.