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
  • 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: [email protected].
  • 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: [email protected].
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.
Products