New type of metalloproteinase inhibitor

Design and synthesis of new phosphonamide-based hydroxamic acids

Masaaki Sawa, Takao Kiyoi, Kiriko Kurokawa, Hiroshi Kumihara, Minoru Yamamoto, Tomohiro Miyasaka, Yasuko Ito, Ryoichi Hirayama, Tomomi Inoue, Yasuyuki Kirii, Eiji Nishiwaki, Hiroshi Ohmoto, Yu Maeda, Etsuko Ishibushi, Yoshimasa Inoue, Kohichiro Yoshino, Hirosato Kondo

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

A series of phosphonamide-based hydroxamate derivatives were synthesized, and the inhibitory activities were evaluated against various metalloproteinases in order to clarify its selectivity profile. Among the four diastereomeric isomers resulting from the chirality at the C-3 and P atoms, the compound with a (R,R)-configuration both at the C-3 position and the phosphorus atom was found to be potently active, while the other diastereomeric isomers were almost inactive. A number of (R,R)-compounds synthesized here exhibited broad spectrum activities with nanomolar Ki values against MMP-1, -3, -9, and TACE and also showed nanomolar IC50 values against HB-EGF shedding in a cell-based inhibition assay. The modeling study using X-ray structure of MMP-3 suggested the possible binding mode of the phosphonamide-based inhibitors.

Original languageEnglish
Pages (from-to)919-929
Number of pages11
JournalJournal of Medicinal Chemistry
Volume45
Issue number4
DOIs
Publication statusPublished - Feb 14 2002
Externally publishedYes

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Hydroxamic Acids
Metalloproteases
Matrix Metalloproteinases
Phosphorus
Inhibitory Concentration 50
X-Rays
Heparin-binding EGF-like Growth Factor

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

New type of metalloproteinase inhibitor : Design and synthesis of new phosphonamide-based hydroxamic acids. / Sawa, Masaaki; Kiyoi, Takao; Kurokawa, Kiriko; Kumihara, Hiroshi; Yamamoto, Minoru; Miyasaka, Tomohiro; Ito, Yasuko; Hirayama, Ryoichi; Inoue, Tomomi; Kirii, Yasuyuki; Nishiwaki, Eiji; Ohmoto, Hiroshi; Maeda, Yu; Ishibushi, Etsuko; Inoue, Yoshimasa; Yoshino, Kohichiro; Kondo, Hirosato.

In: Journal of Medicinal Chemistry, Vol. 45, No. 4, 14.02.2002, p. 919-929.

Research output: Contribution to journalArticle

Sawa, M, Kiyoi, T, Kurokawa, K, Kumihara, H, Yamamoto, M, Miyasaka, T, Ito, Y, Hirayama, R, Inoue, T, Kirii, Y, Nishiwaki, E, Ohmoto, H, Maeda, Y, Ishibushi, E, Inoue, Y, Yoshino, K & Kondo, H 2002, 'New type of metalloproteinase inhibitor: Design and synthesis of new phosphonamide-based hydroxamic acids', Journal of Medicinal Chemistry, vol. 45, no. 4, pp. 919-929. https://doi.org/10.1021/jm0103211
Sawa, Masaaki ; Kiyoi, Takao ; Kurokawa, Kiriko ; Kumihara, Hiroshi ; Yamamoto, Minoru ; Miyasaka, Tomohiro ; Ito, Yasuko ; Hirayama, Ryoichi ; Inoue, Tomomi ; Kirii, Yasuyuki ; Nishiwaki, Eiji ; Ohmoto, Hiroshi ; Maeda, Yu ; Ishibushi, Etsuko ; Inoue, Yoshimasa ; Yoshino, Kohichiro ; Kondo, Hirosato. / New type of metalloproteinase inhibitor : Design and synthesis of new phosphonamide-based hydroxamic acids. In: Journal of Medicinal Chemistry. 2002 ; Vol. 45, No. 4. pp. 919-929.
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