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

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

  • Bioorg Med Chem Lett. 2023 Nov 10:97:129541. doi: 10.1016/j.bmcl.2023.129541.
Rie Nishikawa-Shimono 1,  Motoi Kuwabara 1,  Sho Fujisaki 1,  Daisuke Matsuda 2,  Mayumi Endo 3,  Masafumi Kamitani 3,  Aya Futamura 1,  Yusaku Nomura 1,  Toru Yamaguchi-Sasaki 1,  Tetsuya Yabuuchi 1,  Chitose Yamaguchi 1,  Nozomi Tanaka-Yamamoto 1,  Shunya Satake 1,  Kumi Abe-Sato 1,  Kosuke Funayama 1,  Mayumi Sakata 3,  Shinji Takahashi 4,  Koga Hirano 4,  Takuya Fukunaga 3,  Yoriko Uozumi 3,  Sayaka Kato 3,  Yunoshin Tamura 3,  Tomoaki Nakamori 3,  Masashi Mima 3,  Chiemi Mishima-Tsumagari 3,  Dai Nozawa 1,  Yudai Imai 1,  Taiji Asami 5
Affiliations

Affiliations

  • 1 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 2 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: d-matsuda@taisho.co.jp.
  • 3 Discovery Technologies Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 4 Pharmacology Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan.
  • 5 Medicinal Chemistry Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama 331-9530, Japan. Electronic address: ta-asami@taisho.co.jp.
PMID: 37952596 DOI: 10.1016/j.bmcl.2023.129541
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.

Keywords

Fragile X syndrome; Indole derivatives; Inhibitor of proMMP-9 activation; Matrix metalloproteinase-9; Structure-based drug design.

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