Prostacyclin (PGI2), a member of the eicosanoid family of lipid mediators, is a major product of arachidonic acid metabolism formed in the vascular endothelium and other tissues. PGI2 mediates its effects primarily through a membrane‐associated G protein‐coupled receptor termed the IP (prostacyclin) receptor[2]. RO1138452 is a potent and selective IP receptor antagonist, which displays high affinity for IP receptors. In human platelets, pKi is 9.3 ± 0.1; in a recombinant IP receptor system, pKi is 8.7 ± 0.06[2].
Functional antagonism of RO1138452 was studied by measuring inhibition of carbaprostacyclin-induced cAMP accumulation in CHO-K1 cells stably expressing the human IP receptor. The antagonist affinities (pKi) of RO1138452 was 9.0 ± 0.06. Selectivity profiles for RO1138452 was determined via a panel of receptor binding and enzyme assays. RO1138452 displayed affinity at imidazoline2 (I2) (8.3) and PAF (7.9) receptors. 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[3]. RO1138452 (1 - 10 mg/kg, i.v.) significantly reduced acetic acid-induced abdominal constrictions. RO1138452 (3-100 mg/kg, p.o.) significantly reduced 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)[2].
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