Discovery and optimization of a biphenylacetic acid series of prostaglandin D2 receptor DP2 antagonists with efficacy in a murine model of allergic rhinitis

Bioorg Med Chem Lett. 2011 Nov 1;21(21):6608-12. doi: 10.1016/j.bmcl.2011.01.024. Epub 2011 Jan 11.

Abstract

Biphenylacetic acid (5) was identified through a library screen as an inhibitor of the prostaglandin D(2) receptor DP2 (CRTH2). Optimization for potency and pharmacokinetic properties led to a series of selective CRTH2 antagonists. Compounds demonstrated potency in a human DP2 binding assay and a human whole blood eosinophil shape change assay, as well as good oral bioavailability in rat and dog, and efficacy in a mouse model of allergic rhinitis following oral dosing.

MeSH terms

  • Animals
  • Biological Availability
  • Disease Models, Animal*
  • Dogs
  • Drug Discovery*
  • Mice
  • Phenylacetates / chemistry
  • Phenylacetates / pharmacokinetics
  • Phenylacetates / pharmacology*
  • Phenylacetates / therapeutic use
  • Rats
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Prostaglandin / antagonists & inhibitors*
  • Rhinitis, Allergic, Perennial / drug therapy*

Substances

  • Phenylacetates
  • Receptors, Immunologic
  • Receptors, Prostaglandin
  • biphenylylacetic acid
  • prostaglandin D2 receptor