Study on selectin blocker. 8. Lead discovery of a non-sugar antagonist using a 3D-pharmacophore model

Yasuyuki Hiramatsu, Takahiro Tsukida, Yoshiyuki Nakai, Yoshimasa Inoue, Hirosato Kondo

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

We have developed a pharmacophore model of a ligand/E-selectin complex to screen drug candidates for selectin blockers. In a series of sugar mimetic studies of the E-selectin ligand, sialyl Lewis X (sLe(x)), we have already found a potent compound, a sulfated Le(x) analogue (1), and also have proposed how compound I binds to E-selectin (Tsujishita, H.; Hiramatsu, Y.; Kondo, N.; Ohmoto, H.; Kondo, H.; Kiso, M.; Hasegawa, A. J. Med. Chem. 1997, 40, 362-369). To find drug candidates that fit into the binding pocket of E- selectin, we constructed an original 3D-pharmacophore model from structural information of a compound 1/E-selectin complex model and screened lead compounds for selectin blockers using a commercially available database ACD- 3D. As a result, we discovered a lead compound (2) containing good selectin inhibitory activity, and in addition, we succeeded to preliminarily optimize it to a more active lead compound (3) with micromolar IC50 values, based on the 3D-pharmacophore model investigation. This methodology using the 3D- pharmacophore model could be applicable as a pre-screen system for selectin blockers.

Original languageEnglish
Pages (from-to)1476-1483
Number of pages8
JournalJournal of Medicinal Chemistry
Volume43
Issue number8
DOIs
Publication statusPublished - Aug 20 2000
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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