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

Hideki Moriyama, Yasuyuki Hiramatsu, Takao Kiyoi, Toshio Achiha, Yoshimasa Inoue, Hirosato Kondo

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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.; Inou, 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) and modification of the spacer unit (4-7), (2) a modification of the tail (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 wome 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.

Original languageEnglish
Pages (from-to)1479-1491
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number6
DOIs
Publication statusPublished - Jan 1 2001
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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