PF-04418948 is a potent and selective EP2 receptor antagonist that inhibited PGE2-induced increases in cAMP with a functional KB of 1.8 nM and attenuated butaprost-induced cutaneous blood flow in rats.
PF-04418948 is an orally active, potent, and selective EP2 receptor antagonist that serves as a useful pharmacological tool for studying EP2 receptor function.
Effect estimate: KB 1.8 nM
BACKGROUND AND PURPOSE: Studies of the role of the prostaglandin EP (2) 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 EP (2) receptor antagonist, PF-04418948 (1- (4-fluorobenzoyl) -3- (6-methoxy-2-naphthyl) oxymethyl azetidine-3-carboxylic acid). EXPERIMENTAL APPROACH: Functional antagonist potency was assessed in cell-based systems expressing human EP (2) 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 EP (2) receptor function in vivo was tested in rats. KEY RESULTS: PF-04418948 inhibited prostaglandin E (2) (PGE (2) ) -induced increase in cAMP in cells expressing EP (2) 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 PGE (2) -induced relaxation curve with a K (B) of 2. 5 nM and an apparent K (B) of 1. 3 nM respectively. Reversal of the PGE (2) -induced relaxation in the mouse trachea by PF-04418948 produced an IC (50) value of 2. 7 nM. Given orally, PF-04418948 attenuated the butaprost-induced cutaneous blood flow response in rats. PF-04418948 was selective for EP (2) receptors over homologous and unrelated receptors, enzymes and channels. CONCLUSIONS AND IMPLICATIONS: PF-04418948 is an orally active, potent and selective surmountable EP (2) receptor antagonist that should aid further elaboration of EP (2) receptor function.
Forselles et al. (2011) studied Pharmacological characterization of EP2 receptor antagonist. PF-04418948 was evaluated on Inhibition of PGE2-induced increase in cAMP in cells expressing EP2 receptors (KB 1.8 nM). PF-04418948 is a potent and selective EP2 receptor antagonist that inhibited PGE2-induced increases in cAMP with a functional KB of 1.8 nM and attenuated butaprost-induced cutaneous blood flow in rats.