Pharmacologic profile of UR-7247, an orally active angiotensin II AT(1) receptor antagonist, in healthy volunteers

This study was conducted to assess the pharmacologic properties of the new orally active angiotensin II subtype 1 (AT(1)) antagonist UR-7247, a produc t with a half-life >100 h in humans. The experiment was designed as an open -label, single-dose administration study with four parallel groups of four healthy men receiving increasing single oral doses (2.5, 5, and 10 mg) of U R-7247 or losartan, 100 mg. Angiotensin II receptor blockade was investigat ed less than or equal to 96 h after drug intake, with three independent met hods [i.e., the inhibition of blood pressure (BP) response to exogenous Ang II, an in vitro Ang II-receptor assay (RRA), and the reactive increase in plasma angiotensin II. Plasma drug levels also were measured. The degree of blockade observed in vivo was statistically significant less than or equal to 96 h with all UR-7247 doses for diastolic BP (p < 0.05) and less than o r equal to 48 h for systolic BP. The maximal inhibition achieved with 10 mg UR-7247 was measured 6-24 h after drug intake and reached 54 +/- 17% and 4 8 +/- 20% for diastolic and systolic responses, respectively. Losartan, 100 mg, induced a,greater short-term AT(1)-receptor blockade than 2.5- and 5.0 -mg doses of UR-7247 (p < 0.001 for diastolic BP), but the UR-7247 effect w as longer lasting. In vivo, no significant difference was observed between 10 mg UR-7247 and 100 mg losartan 4 h after drug intake, but in vitro,the b lockade achieved with 100 mg losartan was higher than that seen with UR-724 7. Finally, the results confirm that UR-7247 has a very long plasma elimina tion half-life, which may be due to a high but also tight binding to protei n binding sites. In conclusion, UR-7247 is a long-lasting, well-tolerated A T, receptor in healthy subjects.