1. Academic Validation
  2. 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.
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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