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

Background and Purpose: Research on the role of the prostaglandin EP(2) receptor has been limited due to the lack of potent and selective antagonists. In this study, we present the in vitro and in vivo pharmacological characterization of a novel EP(2) receptor antagonist, PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid).

Experimental Approach: The functional antagonist potency of PF-04418948 was evaluated in cell-based systems expressing human EP(2) receptors and native tissue preparations from human, dog, and mouse. Its selectivity was tested against related receptors and a broad panel of GPCRs, ion channels, and enzymes. The ability of PF-04418948 to block EP(2) receptor function in vivo was also examined in rats.

Key Results: PF-04418948 inhibited prostaglandin E(2) (PGE(2))-induced increases in cAMP in EP(2)-expressing cells, with a functional K(B) value of 1.8 nM. In human myometrium, PF-04418948 shifted the butaprost-induced inhibition of electrical field stimulation-induced contractions to the right, with an apparent K(B) of 5.4 nM. In dog bronchioles and mouse trachea, PF-04418948 similarly shifted the PGE(2)-induced relaxation curves to the right, with K(B) values of 2.5 nM and 1.3 nM, respectively. Reversal of PGE(2)-induced relaxation in the mouse trachea produced an IC(50) of 2.7 nM. When administered orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. Importantly, PF-04418948 was highly selective for EP(2) receptors compared to homologous and unrelated receptors, enzymes, and ion channels.

Conclusions and Implications: PF-04418948 is a potent, selective, and orally active surmountable EP(2) receptor antagonist. Its properties make it a valuable tool for further investigation of EP(2) receptor function.