RO1138452

RO1138452 is a potent and selective IP (prostacyclin) receptor antagonist. RO1138452 displays high affinity for IP receptors. In human platelets, pK_i is 9.3±0.1; in a recombinant IP receptor system, pK_i is 8.7±0.06. IC50 & Target: IC50: 7 nM (rat I₂ receptor), 52.9 nM (rabbit PAF), 724 nM (human α_2A adrenoceptor), 3280 nM (rat α_1B adrenoceptor), 1450 nM (human muscarinic M₄ receptor), 2220 nM (human muscarinic M₂ receptor), 2570 nM (human muscarinic M₁ receptor), 3110 nM (human muscarinic M₅ receptor), 1130 nM (rat 5-HT_1B receptor ), 1190 nM (pig 5-HT_2C receptor), 3040 nM (rat 5-HT_2A receptor), 8580 nM (human 5-HT_1A receptor ), 8910 nM (guinea-pig 5-HT₄ receptor)^[1]
pKi: 5.87 (rat α_1B adrenoceptor), 6.49 (human α_2A adrenoceptor), 8.33 (rat I₂ receptor), 5.66 (human muscarinic M₁ receptor), 5.81 (human muscarinic M₅ receptor), 5.88 (human muscarinic M₂ receptor), 6.14 (human muscarinic M₄ receptor), 7.9 (rabbit PAF), 5.35 (guinea-pig 5-HT₄ receptor ), 5.37 (human 5-HT_1A receptor ), 5.71 (rat 5-HT_2A receptor) , 6.11 (rat 5-HT_1B receptor), 6.11 (pig 5-HT_2C receptor)^[1] In Vitro: RO1138452 is IP receptor antagonist. The pIC₅₀ values of RO1138452 in attenuating cAMP accumulation is 7.0±0.07. Functional antagonism of RO1138452 is studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinity (pK_i) of RO1138452 is 9.0±0.06. Selectivity profiles for RO1138452 are determined via a panel of receptor binding and enzyme assays. RO1138452 displays affinity at imidazoline₂ (I₂) (8.3) and platelet activating factor (PAF) (7.9) receptors^[1]. RO1138452 (10 pM-10 μM) added to cells concurrently with a fixed concentration of Taprostene (1 μM) prevents, in a concentration-dependent manner, the inhibition of CXCL9 and CXCL10 release, with p[A]₅₀ (molar) values of -8.73±0.11 and -8.47±0.16 (p>0.05), respectively^[2]. In Vivo: RO1138452 is a potent and selective antagonist for both human and rat IP receptors and that is possesses analgesic and anti-inflammatory potential. RO1138452 (1-10?mg/kg, i.v.) significantly reduces acetic acid-induced abdominal constrictions. RO1138452 (3-100?mg/kg, p.o.) significantly reduces carrageenan-induced mechanical hyperalgesia and edema formation. One?hour after administration of RO1138452 (5?mg/kg, i.v.) to rats, the total plasma concentration is 0.189 ?μg/mL, whereas the free plasma concentrations is calculated to be 0.009?μg/mL (28 nM)^[1].