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

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


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.

MeSH terms

  • Alprostadil / analogs & derivatives
  • Alprostadil / pharmacology
  • Animals
  • Azetidines / pharmacology*
  • Bronchioles / drug effects
  • Bronchioles / physiology
  • CHO Cells
  • Carboxylic Acids / pharmacology*
  • Cricetinae
  • Cyclic AMP / metabolism
  • Dinoprostone / pharmacology
  • Dogs
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle Contraction / drug effects*
  • Myometrium / drug effects
  • Myometrium / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E, EP2 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP2 Subtype / metabolism
  • Regional Blood Flow / drug effects
  • Skin / blood supply
  • Skin / drug effects
  • Trachea / drug effects
  • Trachea / physiology


  • Azetidines
  • Carboxylic Acids
  • Receptors, Prostaglandin E, EP2 Subtype
  • Cyclic AMP
  • Alprostadil
  • butaprost
  • 1-(4-fluorobenzoyl)-3-(((6-methoxy-2-naphthyl)oxy)methyl)azetidine-3-carboxylic acid
  • Dinoprostone