Substituted indole-1-acetic acids as potent and selective CRTh2 antagonists-discovery of AZD1981

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6288-92. doi: 10.1016/j.bmcl.2011.08.124. Epub 2011 Sep 5.

Abstract

Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).

MeSH terms

  • Acetates / chemistry
  • Acetates / pharmacology*
  • Drug Discovery*
  • Humans
  • Indoleacetic Acids / chemistry
  • Indoleacetic Acids / pharmacology*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Neutrophils / drug effects
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Prostaglandin / antagonists & inhibitors*

Substances

  • Acetates
  • Indoleacetic Acids
  • Indoles
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • AZD1981
  • prostaglandin D2 receptor