Switching between agonists and antagonists at CRTh2 in a series of highly potent and selective biaryl phenoxyacetic acids

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3616-21. doi: 10.1016/j.bmcl.2011.04.101. Epub 2011 Apr 28.

Abstract

A novel series of biaryl phenoxyacetic acids was discovered as potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). A hit compound 4 was discovered from high throughput screening. Modulation of multiple aryl substituents afforded both agonists and antagonists, with small changes often reversing the mode of action. Understanding the complex SAR allowed design of potent antagonists such as potential candidate 34.

MeSH terms

  • Acetates / chemical synthesis*
  • Acetates / chemistry
  • Acetates / pharmacology
  • Animals
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rats
  • Receptors, Immunologic / agonists*
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Prostaglandin / agonists*
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Acetates
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • prostaglandin D2 receptor
  • phenoxyacetic acid