Four G protein-coupled receptors, EP1-4, initiate cellular signaling in response to prostaglandin PGE2. The receptor EP1 acts via Gαq to evoke diverse effects, including renal vasoconstriction, bronchoconstriction, hyperalgesia, allodynia, gastric protection, hyperthermia, and sleep inhibition. GW 848687X is a potent and selective EP1 receptor antagonist (IC50 = 2.5 nM).1 It has >400-fold selectivity for EP1 relative to the other EP receptor subtypes, the PGD2 receptor, DP1, and the prostacyclin receptor, IP. GW 848687X has 30-fold selectivity over the thromboxane A2 receptor, TP, acting as a functional antagonist at this receptor at higher levels.1 Its actions against the FP and CRTH2/DP2 receptors have not been characterized. In vivo, GW 848687X has an excellent oral pharmacokinetic profile, with oral bioavailability at 54% in rats and 53% in dogs with a half-life of two hours in both species.1 In a rat model of chronic inflammatory joint pain, GW 848687X shows complete anti-hyperalgesic activity with an ED50 value of 1.3 mg/kg.1
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Giblin, G.M.P., Bit, R.A., Brown, S.H., et al. The discovery of 6-[2-(5-chloro-2{[(2,4-difluorophenyl)-methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain. Bioorg Med Chem Lett17385-389(2007).
Stasch, J., Alonso-Alija, C., Apeler, H., et al. Pharmacological actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vitro studies. Br J Pharmacol135333-343(2002).
Stasch, J., Dembowsky, K., Perzborn, E., et al. Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol135344-355(2002).
Evgenov, O.V., Kohane, D.S., Bloch, K.D., et al. Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med1761138-1145(2007).
Giblin, G.M.P., Bit, R.A., Brown, S.H., et al. The discovery of 6-[2-(5-chloro-2{[(2,4-difluorophenyl)-methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain. Bioorg Med Chem Lett17385-389(2007).