Convergence Pharmaceuticals.

Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.

sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP 4 receptors with additional human TP receptor affinity. 2 At recombinant human prostanoid EP 4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE 2 concentration-effect (E/[A]) curves resulting in an affinity (pK b ) estimate of 7.970.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 3 In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE 2 E/[A] curves (pK b ¼ 9.270.2; slope ¼ 1). 4 GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 mM) produced 100% inhibition of U-46619 (EC 100 )-induced aggregation (approximate pA 2 B7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 mM) did not displace U-46619 E/[A] curves indicating an affinity of o5.0 for rabbit and guinea-pig prostanoid TP receptors. 5 In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH 2 , EP 2 , EP 3 , IP and FP receptors. At prostanoid EP 1 receptors, GW627368X was an antagonist with a pA 2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP 2 receptors the pA 2 of GW627368X was o5.0. 6 In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP 4 and TP receptors (pK i ¼ 7.070.2 (n ¼ 10) and 6.8 (n ¼ 2), respectively). Affinity for all other human prostanoid receptors was o5.3. 7 GW627368X will be a valuable tool to explore the role of the prostanoid EP 4 receptor in many physiological and pathological settings.