Discovery of novel indole derivatives as potent and selective inhibitors of proMMP-9 activation

Bioorg Med Chem Lett. 2023 Nov 10:129541. doi: 10.1016/j.bmcl.2023.129541. Online ahead of print.ABSTRACTMatrix 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.PMID:37952596 | DOI:10.1016/j.bmcl.2023.129541

Source: Bioorganic and Medicinal Chemistry Letters - November 12, 2023 Category: Chemistry Authors: Rie Nishikawa-Shimono Motoi Kuwabara Sho Fujisaki Daisuke Matsuda Mayumi Endo Masafumi Kamitani Aya Futamura Yusaku Nomura Toru Yamaguchi-Sasaki Tetsuya Yabuuchi Chitose Yamaguchi Nozomi Tanaka-Yamamoto Shunya Satake Kumi Abe-Sato Kosuke Funayama Mayumi S Source Type: research