Identification of novel plasminogen activator inhibitor-1 inhibitors with improved oral bioavailability: Structure optimization of N-acylanthranilic acid derivatives

Nagahisa Yamaoka, Kenji Murano, Hidehiko Kodama, Akihisa Maeda, Takashi Dan, Tetsuo Nakabayashi, Toshio Miyata, Kanji Meguro

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Novel plasminogen activator inhibitor-1 (PAI-1) inhibitors with highly improved oral bioavailability were discovered by structure-activity relationship studies on N-acyl-5-chloroanthranilic acid derivatives. Because lipophilic N-acyl groups seemed to be important for the anthranilic acid derivatives to strongly inhibit PAI-1, synthesis of compounds in which 5-chloroanthranilic acid was bound to a variety of highly lipophilic moieties with appropriate linkers was investigated. As the result it appeared that some of the derivatives possessing aryl- or heteroaryl-substituted phenyl groups in the acyl chain had potent in vitro PAI-1 inhibitory activity. Oral absorbability of typical compounds was also evaluated in rats, and compounds 40, 55, 60 and 76 which have diverse chemical structure with each other were selected for further pharmacological evaluation.

Original languageEnglish
Pages (from-to)809-813
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume28
Issue number4
DOIs
Publication statusPublished - 2018 Feb 15

Keywords

  • N-Acylanthranilic acid derivatives
  • Oral bioavailability
  • PAI-1 inhibitor
  • Plasminogen activator inhibitor-1 (PAI-1)
  • Structure-activity relationship

ASJC Scopus subject areas

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

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