On mast cells, prostaglandin D2 (PGD2) and its receptor D prostanoid receptor 2 (DP2) have been linked to the development of allergic inflammation, which has spurred interest in identifying more potent and selective antagonists of this receptor to treat asthma and related disorders. Pettipher et al. describe the pharmacological profile of (5-fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459), an indole-1-acetic acid derivative and a potent and selective DP2 antagonist. OC000459 potently displaces PGD2 from DP2 but does not interfere with the ligand-binding properties or functional activities of other prostanoid receptors. OC000459 competitively antagonized eosinophil shape-change responses induced by PGD2. OC000459 inhibited activation of T helper 2 (Th2) cells and eosinophils in response to supernatants from IgE/anti-IgE activated human mast cells. OC000459 was orally bioavailable in rats and inhibited blood eosinophilia and airway eosinophilia in response to 13,14-dihydro-15-keto-PGD2. OC000459 is a highly potent, selective, and orally active DP2 antagonist that inhibits mast cell-dependent activation of Th2 cells and eosinophils. This compound is proving to be an excellent tool in defining the role of DP2 in asthma and related allergic disorders. It is currently being evaluated in phase IIb trials and has the potential to be one of a new class of oral anti-inflammatory agents to treat allergic disorders.
See article at J Pharmacol Exp Ther 2012, 340:473–482.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics