In vitro and in vivo characterization of PF‐04418948, a novel, potent and selective prostaglandin EP2 receptor antagonist

Abstract

BACKGROUND AND PURPOSE Studies of the role of the prostaglandin EP₂ receptor) have been limited by the availability of potent and selective antagonist tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP₂ receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid). EXPERIMENTAL APPROACH Functional antagonist potency was assessed in cell-based systems expressing human EP₂ receptors and native tissue preparations from human, dog and mouse. The selectivity of PF-04418948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes. The ability of PF-04418948 to pharmacologically block EP₂ receptor function in vivo was tested in rats. KEY RESULTS PF-04418948 inhibited prostaglandin E₂ (PGE₂)-induced increase in cAMP in cells expressing EP₂ receptors with a functional K_B value of 1.8 nM. In human myometrium, PF-04418948 produced a parallel, rightward shift of the butaprost-induced inhibition of the contractions induced by electrical field stimulation with an apparent K_B of 5.4 nM. In dog bronchiole and mouse trachea, PF-04418948 produced parallel rightward shifts of the PGE₂-induced relaxation curve with a K_B of 2.5 nM and an apparent K_B of 1.3 nM respectively. Reversal of the PGE₂-induced relaxation in the mouse trachea by PF-04418948 produced an IC₅₀ value of 2.7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP₂ receptors over homologous and unrelated receptors, enzymes and channels. CONCLUSIONS AND IMPLICATIONS PF-04418948 is an orally active, potent and selective surmountable EP₂ receptor antagonist that should aid further elaboration of EP₂ receptor function. LINKED ARTICLE This article is commented on by Birrell and Nials, pp. 1845–1846 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01494.x