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. 2011 Dec;164(7):1847-56.
doi: 10.1111/j.1476-5381.2011.01495.x.

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

Affiliations

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

K J af Forselles et al. Br J Pharmacol. 2011 Dec.

Erratum in

  • Br J Pharmacol. 2012 Jun;166(3):1192. Dosage error in article text

Abstract

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)oxy]methyl} 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.

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Figures

Figure 1
Figure 1
The chemical structure of PF-04418948 (1-(4-fluorobenzoyl)-3-{[(6-methoxy-2-naphthyl)oxy]methyl} azetidine-3-carboxylic acid).
Figure 2
Figure 2
Butaprost (n = 5) caused concentration-dependent inhibition of the EFS-induced contraction of the non-pregnant human myometrium. PF-04418948 (100 nM, n = 4) produced rightward parallel shifts of the butaprost concentration–effect curve.
Figure 3
Figure 3
Antagonism by PF-04418948 of the PGE2-induced relaxation of carbachol pre-contracted rings of dog bronchioles (n = 4). (A) PF-04418948 (3–100 nM) produced concentration-dependent rightward parallel shifts of the PGE2 curve. (B) The corresponding Clark plot is consistent with simple competitive antagonism.
Figure 4
Figure 4
Antagonism by PF-04418948 of the PGE2-induced relaxation of carbachol pre-contracted rings of mouse trachea (n = 26). PF-04418948 (1 and 3 nM) caused concentration-dependent rightward parallel shifts of the PGE2 curve.
Figure 5
Figure 5
Increasing concentrations of PF-04418948 reversed the relaxation in rings of mouse trachea induced by 700 nM PGE2 (n = 7).
Figure 6
Figure 6
The effects of orally administered PF-04418948 or vehicle on PGE2 (A) and butaprost (B) induced cutaneous blood flow responses in the rat. (A) PGE2 (3 µg·mL−1, s.c.) was used to induce a cutaneous vasodilatory response and the effect of PF-04418948 (10 mg·kg−1, p.o.) on this response was compared with that of vehicle. Data are normalized to the mean of the final three baseline measurements (mean ± SEM, n = 6). (B) Butaprost (30 µg·mL−1, s.c.) or vehicle was used to induce a cutaneous blood flow response and the effect of PF-04418948 (1 mg·kg−1, 3 mg·kg−1, and 10 mg·kg−1, p.o.), compared with vehicle. Data are normalized to the mean of the final three baseline measurements (mean ± SEM, n = 4). The change in cutaneous blood flow response becomes statistically significant (P < 0.05) over vehicle control at 30 min post-butaprost dose.

Comment in

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