Development and evaluation of ST-1829 based on 5-benzylidene-2-phenylthiazolones as promising agent for anti-leukotriene therapy

Eur J Med Chem. 2015 Jan 7;89:503-23. doi: 10.1016/j.ejmech.2014.10.054. Epub 2014 Oct 18.


Different inflammatory diseases and allergic reactions are mediated by leukotrienes, which arise from the oxygenation of arachidonic acid catalyzed by 5-lipoxygenase (5-LO). One promising approach for an effective anti-leukotriene therapy is the inhibition of this key enzyme. This study presents the synthesis and development of a potent and direct 5-LO inhibitor based on the well characterized 5-benzylidene-2-phenylthiazolone C06, whose further pharmacological investigation was precluded due to its low solubility. Through optimization of C06, evaluation of structure-activity relationships including profound assessment of the thiazolone core and consideration of the solubility, the 5-benzyl-2-phenyl-4-hydroxythiazoles represented by 46 (ST-1829, 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol) were developed. Compound 46 showed an improved 5-LO inhibitory activity in cell-based (IC50 values 0.14 μM) and cell-free assays (IC50 values 0.03 μM) as well as a prominent enhanced solubility. Furthermore, it kept its promising inhibitory potency in the presence of blood serum, excluding excessive binding to serum proteins. These facts combined with the non-cytotoxic profile mark a major step towards an effective anti-inflammatory therapy.

Keywords: 5-Lipoxygenase; Anti-leukotriene therapy; Hydroxythiazoles; Inflammation; Solubility; Structure–activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Humans
  • Leukotriene Antagonists / chemical synthesis
  • Leukotriene Antagonists / chemistry
  • Leukotriene Antagonists / pharmacology*
  • Leukotrienes / metabolism*
  • Lipoxygenase Inhibitors / chemical synthesis
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • 5-(4-chlorobenzyl)-2-p-tolylthiazol-4-ol
  • 5-(4-methoxybenzylidene)-2-p-tolylthiazol-4(5H)-one
  • Leukotriene Antagonists
  • Leukotrienes
  • Lipoxygenase Inhibitors
  • Thiazoles
  • Arachidonate 5-Lipoxygenase