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

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.

• Authors: Jill M Scott, Christopher Baccei, Gretchen Bain, Alex Broadhead, Jilly F Evans, Patrick Fagan, John H Hutchinson, Christopher King, Daniel S Lorrain, Catherine Lee, Peppi Prasit, Pat Prodanovich, Angelina Santini, Brian A Stearns
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 21 Pg. 6608-12 (Nov 01 2011) ISSN: 1464-3405 [Electronic] England
• PMID: 21958540 (Publication Type: Journal Article)
• Copyright: Copyright © 2011. Published by Elsevier Ltd.

Chemical References

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

Topics

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