4,5-Diarylisoxazol-3-carboxylic acids: A new class of leukotriene biosynthesis inhibitors potentially targeting 5-lipoxygenase-activating protein (FLAP)


Banoğlu E., Celikoglu E., Voelker S., Olğaç A., Gerstmeier J., Garscha U., ...More

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol.113, pp.1-10, 2016 (Peer-Reviewed Journal) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 113
  • Publication Date: 2016
  • Doi Number: 10.1016/j.ejmech.2016.02.027
  • Journal Name: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
  • Journal Indexes: Science Citation Index Expanded, Scopus
  • Page Numbers: pp.1-10
  • Keywords: Inflammation, Leukotrienes, 5-lipoxygenase, 5-lipoxygenase-activating protein, Isoxazole, INFLAMMATORY DISEASES, MYELOID-LEUKEMIA, ATHEROSCLEROSIS, ASTHMA, CANCER, DISCOVERY, DESIGN, CELLS, TOLERABILITY, NEUTROPHILS

Abstract

In this article, we report novel leukotriene (LT) biosynthesis inhibitors that may target 5-lipoxygenase-activating protein (FLAP) based on the previously identified isoxazole derivative (8). The design and synthesis was directed towards a subset of 4,5-diaryl-isoxazole-3-carboxylic acid derivatives as LT biosynthesis inhibitors. Biological evaluation disclosed a new skeleton of potential anti-inflammatory agents, exemplified by 39 and 40, which potently inhibit cellular 5-LO product synthesis (IC50 = 0.24 mu M, each) seemingly by targeting FLAP with weak inhibition on 5-LO (IC50 > 8 mu M). Docking studies and molecular dynamic simulations with 5-LO and FLAP provide valuable insights into potential binding modes of the inhibitors. Together, these diaryl-isoxazol-3-carboxylic acids may possess potential as leads for development of effective anti-inflammatory drugs through inhibition of LT biosynthesis. (C) 2016 Elsevier Masson SAS. All rights reserved.