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Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings.

Authors
  • Moriyama, H
  • Hiramatsu, Y
  • Kiyoi, T
  • Achiha, T
  • Inoue, Y
  • Kondo, H
Type
Published Article
Journal
Bioorganic & Medicinal Chemistry
Publisher
Elsevier
Publication Date
Jun 01, 2001
Volume
9
Issue
6
Pages
1479–1491
Identifiers
PMID: 11408166
Source
Medline
License
Unknown

Abstract

As a part of study of selectin blockers, we have already reported that a non-sugar selectin antagonist (3) was successfully discovered using a computational screening (Hiramatsu, Y.; Tsukida, T.; Nakai, Y.; Inoue, Y.; Kondo, H. J. Med. Chem. 2000, 43, 1476). To investigate the SARs of compound 3 against E-, P-, and L-selectins, we synthesized the derivatives of compound 3 and evaluated their inhibitory activities toward selectin bindings. The structural diversity of compound 3 contained the following: (1) a modification of the spacer unit (4--7), (2) a modification of the tail unit (8--11), (3) a modification of the head unit (12--18). As a result, it was found that a non-sugar based selectin blocker (3) could be a potential lead compound for E-, P-, and L-selectin blockers and some of the derivatives showed broad and/or selective inhibitory activities toward the E-, P-, and L-selectins. In addition, it was found that the experimental evidence well supported that the computational screening using 3D-pharmacophore model could be useful methodology to find out a new lead for the several type of selectin blockers, which included a broad and/or a selective inhibitor.

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