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

• Published in: Bioorganic & medicinal chemistry letters Vol. 97; p. 129541
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-01-2024
• Subjects: Fragile X syndrome; Indole derivatives; Inhibitor of proMMP-9 activation; Matrix metalloproteinase-9; Structure-based drug design; Matrix metalloproteinase-9; Inhibitor of proMMP-9 activation; Structure-based drug design; Fragile X syndrome; Indole derivatives
• DOI: 10.1016/j.bmcl.2023.129541
• EISSN: 1464-3405
• ISSN: 0960-894X

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•HTS of our internal compound library led to the discovery of two hit compounds.•The two hit compounds were merged to provide a lead with proMMP-9 inhibition.•Replacement with a fused six-seven membered ring improved the proMMP-9 inhibition.•SBDD and optimization led to a highly potent clinical candidate compound.
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.