PF 04418948

PF-04418948 is an orally active, potent and selective prostaglandin EP2 receptor antagonist with an IC50 of 16 nM.

Prostaglandin E2 (PGE2) induces distinct responses through four different ‘E prostanoid’ (EP) receptors. EP2 is a G protein-coupled receptor which signals preferentially through Gs proteins. It is far less active at other prostanoid receptors, including other EP receptors. PF-04418948 can be used in both cells and tissues.

In vitro, PF-04418948 inhibited prostaglandin E2 (PGE2)-induced growth in cAMP with a functional KB value of 1.8 nM in cells expressing EP2 receptors.

In vivo, in the case of human myometrium, PF-04418948 caused a parallel, rightward shift of the butaprost-induced inhibition of the contractions that was induced by electrical field stimulation with an apparent KB of 5.4 nM. In dog bronchiole and mouse trachea, it produced the same shifts of the PGE2-induced relaxation curve with a KB of 2.5 nM and an apparent KB of 1.3 nM respectively. Moreover, in the mouse trachea, reversal of the PGE2-induced relaxation by PF-04418948 produced an IC50 value of 2.7 nM.In rats, PF-04418948 significantly weakens the effects of the EP2-selective agonist butaprost on cutaneous blood flow when given orally. It was selective for EP2 receptors over homologous and unrelated receptors, enzymes and channels.

References:

1: af Forselles KJ, Root J, Clarke T, Davey D, Aughton K, Dack K, Pullen N. 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. Erratum in: Br J Pharmacol. 2012 Jun;166(3):1192. Dosage error in article text. PubMed PMID: 21595651; PubMed Central PMCID: PMC3246710.

2. Birrell MA, Maher SA, Buckley J, Dale N, Bonvini S, Raemdonck K, Pullen N, Giembycz MA, Belvisi MG. Selectivity profiling of the novel EP2 receptor antagonist, PF-04418948, in functional bioassay systems: atypical affinity at the guinea pig EP2 receptor. Br J Pharmacol. 2013 Jan;168(1):129-38. doi: 10.1111/j.1476-5381.2012.02088.x. PubMed PMID: 22747912; PubMed Central PMCID: PMC3570009.

3. Säfholm J, Dahlén SE, Delin I, Maxey K, Stark K, Cardell LO, Adner M. PGE2 maintains the tone of the guinea pig trachea through a balance between activation of contractile EP1 receptors and relaxant EP2 receptors. Br J Pharmacol. 2013 Feb;168(4):794-806. doi: 10.1111/j.1476-5381.2012.02189.x. PubMed PMID: 22934927; PubMed Central PMCID: PMC3631371