in rats: 3, 10, 30 and 100 mg/kg

In human platelets, affinities of RO1138452 and RO3244794 were 9.3±0.1 and 7.7±0.03, respectively. In the recombinant IP receptor system, the affinities of RO1138452 and RO3244794 were estimated to be 8.7±0.1 and 6.9±0.1, respectively. In order to determine whether RO1138452 behaves as functional antagonists of the IP receptor, it was tested whether this compound could block cAMP accumulation in CHO-K1 cells overexpressing the human IP receptor in 4–5 independent experiments. cPGI2 was used as the agonist to stimulate the IP receptor in these cells and showed a potency (pEC50) of 10±0.08. For cAMP inhibition experiments, 10 nM cPGI2 was used to drive the cAMP signalling pathway after incubating cells with various concentrations of RO1138452. Consistent with the binding affinities, RO1138452 was a more potent antagonist of the human IP receptor than RO3244794. The pIC50 values of RO1138452 in attenuating cAMP accumulation was 7.0±0.07.