title: Pharmacologic profile of UR-7247, an orally active angiotensin II AT1 receptor antagonist, in healthy volunteers. p6.
abstract: This study was conducted to assess the pharmacologic properties of the new orally active angiotensin II subtype I (AT1) antagonist UR-7247, a product 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 UR-7247 or losartan, 100 mg. Angiotensin II receptor blockade was investigated < or =96 h after drug intake, with three independent methods [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 < or = 96 h with all UR-7247 doses for diastolic BP (p < 0.05) and < or =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 48 +/- 20% for diastolic and systolic responses, respectively. Losartan, 100 mg, induced a greater short-term AT1-receptor blockade than 2.5- and 5.0-mg doses of UR-7247 (p < 0.001 for diastolic BP), but the UR-7247 effect was 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 blockade achieved with 100 mg losartan was higher than that seen with UR-7247. Finally, the results confirm that UR-7247 has a very long plasma elimination half-life, which may be due to a high but also tight binding to protein binding sites. In conclusion, UR-7247 is a long-lasting, well-tolerated AT1 receptor in healthy subjects.
authors.affiliation: Division of Hypertension and Vascular Medicine, University Hospital of Lausanne, Switzerland. Marc.Maillard@chuv.hospvd.ch
authors.forename: M P
authors.initials: MP
authors.lastname: Maillard
authors.forename: J
authors.initials: J
authors.lastname: Rossat
authors.forename: J
authors.initials: J
authors.lastname: Nussberger
authors.forename: J
authors.initials: J
authors.lastname: Ramis
authors.forename: C
authors.initials: C
authors.lastname: Pontes
authors.forename: M
authors.initials: M
authors.lastname: Burnier
authors.forename: H R
authors.initials: HR
authors.lastname: Brunner
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000804:Angiotensin II / Q000097:blood / Q000378:metabolism; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019808:Losartan / Q000494:pharmacology; D008297:Male; D011720:Pyrazoles / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
chemical_list: D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D011720:Pyrazoles; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C406274:UR 7247; D000804:Angiotensin II; D019808:Losartan