Structure-activity relationship of benzodiazepine derivatives as LXXLL peptide mimetics that inhibit the interaction of vitamin D receptor with coactivators

Yusuke Mita, Kosuke Dodo, Tomomi Noguchi-Yachide, Yuichi Hashimoto, Minoru Ishikawa

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Suppression of vitamin D receptor (VDR)-mediated transcription is expected to be of therapeutic value in Paget's disease of bone. It is known that interaction between VDR and coactivators is necessary for VDR transactivation, and the interaction occurs when VDR recognizes an LXXLL peptide motif of coactivators. We previously reported that benzodiazepine derivatives designed as LXXLL peptide mimetics inhibited the interaction of VDR and coactivators, and reduced VDR transcription. Here, we investigated the structure-activity relationship of 7- and 8-substituted benzodiazepine derivatives, and established that the amino group at the 8-position is critical for the inhibitory activity.

Original languageEnglish
Pages (from-to)993-1005
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number4
DOIs
Publication statusPublished - 2013 Feb 15
Externally publishedYes

Keywords

  • Antagonist
  • Cofactor
  • LXXLL
  • Non-peptide
  • Nuclear receptor
  • Protein interaction inhibitor
  • Structure-activity relationship
  • Vitamin D

ASJC Scopus subject areas

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

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