In vitro and in vivo characterization of PF-044189948, a novel, potent and selective prostaglandin EP2 receptor antagonist

BACKGROUND AND PURPOSE Studies of the role of the prostaglandni EP2 receptor) have been Nimrted by the avarNabrlity of potent and selectrve antagonrst tools. Here we describe the in vitro/in vivo pharmacological characterization of a novel EP2 receptor antagonist, PF-0441 8948 (1 (4$l azetidine3carboxylic acid). EXPERIMANTAL APPROACH Functronal antagonrst potency was assessed in cell based systems expressrng human EP2 receptors and natrve trssue preparations from human, dog and mouse. The selectivity of PFO441 8948 was assessed against related receptors and a panel of GPCRs, ion channels and enzymes The ability of PFO441 8948 to pharmacologically block EP, receptor function in vivo was tested ri rats. KEY RESULTS PEO441 8948 inhibited prostaglandirr E2 (PGE2)induced increase in cAMP in cells expressing EP2 receptors with a functional KB value of 1 .8 nM. In human myometrium, PEO441 8948 produced a parallel, rightward shift of the butaprost.induced nhibrtion of the contractrons nduced by electncal field stimulation wrth an apparent KB of 5 4 nM In dog bronchrole and mouse trachea, PEO441 8948 produced parallel rightward shifts of the PGE2.lnduced relaxation curve with a KF of 2.5 nM and an apparent K5 of 1 .3 nM respectively. Reversal of the PGE2induced relaxation in the mouse trachea by PEO441 8948 produced an IC50 value of 2.7 nM, Given orally, PEO441 8948 attenuated the butaprostinduced cutaneous blood flow response in rats PEO441 8948 was selective for EP2 receptors over homologous and unrelated receptors, enzymes and channels. CONCLUSIONS AND IMPLICATIONS PFsj441 8948 is an orally actrve, potent arid selective surnnrounrtable EP2 receptor antagonist that should aid further elaboration of EP2 receptor function.