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SC-52458, an orally active angiotensin II-receptor antagonist: inhibition of blood pressure response to angiotensin II challenges and pharmacokinetics in normal volunteers. 1997

M Hagmann, and J Nussberger, and R B Naudin, and T S Burns, and A Karim, and B Waeber, and H R Brunner
Division of Hypertension, University Hospital, Lausanne, Switzerland.

This study was designed to assess in normal volunteers the potency, efficacy, and tolerability of the new nonpeptidic, orally active, angiotensin (Ang) II subtype 1 (AT1)-receptor antagonist SC-52458. After a randomized, single-blind, placebo-controlled protocol, two groups of eight healthy men ingested placebo or increasing single oral doses (10, 25, and 50 mg or 100, 150, and 200 mg) of SC-52458. Finger blood pressure (BP) was continuously monitored (Finapres), and BP response to repeated intravenous challenges with Ang II was compared with baseline BP response to the same dose of Ang II. Up to 24 h after drug intake, effects on plasma renin activity (PRA), Ang II, and aldosterone and pharmacokinetics were estimated. One, 4, and 10 h after the 200-mg dose, diastolic BP response to Ang II challenges was decreased from 30.3 to 2.6 mm Hg (mean +/- SEM; n = 8; i.e., to 8.3 +/- 1.1% of baseline response), 10.1 mm Hg (35.4 +/- 1.8%), and 17.5 mm Hg (58.7 +/- 1.8%), respectively. SC-52458 produced dose-related increases in PRA and Ang II concentrations < or = 10 h after drug intake. Plasma aldosterone concentrations tended to be decreased for < or = 24 h after SC-52458 doses of > or = 100 mg. No drug-related side effects were observed. The pharmacokinetics were linear over the dose range of 10-150 mg (t1/2 = 1.14-2.39 h). Efficacy was dose dependent, with a peak effect after 1 h. In conclusion, the novel AT1-receptor antagonist SC-52458 is well tolerated and orally active. It produces a rapid-onset inhibition of the renin-angiotensin system and reduces BP response to Ang II for > or = 10 h. These characteristics promise strong antihypertensive properties for SC-52458.

UI MeSH Term Description Entries
D007275 Injections, Intravenous Injections made into a vein for therapeutic or experimental purposes. Intravenous Injections,Injection, Intravenous,Intravenous Injection
D008297 Male Males
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D011863 Radioimmunoassay Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Non-immunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation. Radioimmunoassays
D012083 Renin A highly specific (Leu-Leu) endopeptidase that generates ANGIOTENSIN I from its precursor ANGIOTENSINOGEN, leading to a cascade of reactions which elevate BLOOD PRESSURE and increase sodium retention by the kidney in the RENIN-ANGIOTENSIN SYSTEM. The enzyme was formerly listed as EC 3.4.99.19. Angiotensin-Forming Enzyme,Angiotensinogenase,Big Renin,Cryorenin,Inactive Renin,Pre-Prorenin,Preprorenin,Prorenin,Angiotensin Forming Enzyme,Pre Prorenin,Renin, Big,Renin, Inactive
D001794 Blood Pressure PRESSURE of the BLOOD on the ARTERIES and other BLOOD VESSELS. Systolic Pressure,Diastolic Pressure,Pulse Pressure,Pressure, Blood,Pressure, Diastolic,Pressure, Pulse,Pressure, Systolic,Pressures, Systolic
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D006339 Heart Rate The number of times the HEART VENTRICLES contract per unit of time, usually per minute. Cardiac Rate,Chronotropism, Cardiac,Heart Rate Control,Heartbeat,Pulse Rate,Cardiac Chronotropy,Cardiac Chronotropism,Cardiac Rates,Chronotropy, Cardiac,Control, Heart Rate,Heart Rates,Heartbeats,Pulse Rates,Rate Control, Heart,Rate, Cardiac,Rate, Heart,Rate, Pulse
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations

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