Isoquinoline derivatives as potent CRTH2 receptor antagonists: synthesis and SAR

Bioorg Med Chem Lett. 2012 May 1;22(9):3305-10. doi: 10.1016/j.bmcl.2012.03.009. Epub 2012 Mar 10.

Abstract

Synthesis and structure-activity relationship of a novel series of isoquinoline CRTH2 receptor antagonists are described. One of the most potent compounds, TASP0376377 (6m), showed not only potent binding affinity (IC(50)=19 nM) but also excellent functional antagonist activity (IC(50)=13 nM). TASP0376377 was tested for its ability of a chemotaxis assay to show the effectiveness (IC(50)=23 nM), which was in good agreement with the CRTH2 antagonist potency. Furthermore, TASP0376377 showed sufficient selectivity for binding to CRTH2 over the DP1 prostanoid receptor (IC(50)>1 μM) and COX-1 and COX-2 enzymes (IC(50)>10 μM).

MeSH terms

  • Chemotaxis
  • Inhibitory Concentration 50
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Models, Molecular
  • Prostaglandin-Endoperoxide Synthases / chemistry
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Receptors, Prostaglandin / chemistry
  • Structure-Activity Relationship

Substances

  • Isoquinolines
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • prostanoid D receptor 1, human
  • Prostaglandin-Endoperoxide Synthases
  • prostaglandin D2 receptor