SC-52458, AN ORALLY-ACTIVE ANGIOTENSIN II-RECEPTOR ANTAGONIST - INHIBITION OF BLOOD-PRESSURE RESPONSE TO ANGIOTENSIN-II CHALLENGES AND PHARMACOKINETICS IN NORMAL VOLUNTEERS

This study was designed to assess in normal volunteers the potency, ef ficacy, and tolerability of the new nonpeptidic, orally active, angiot ensin (Ang) II subtype 1 (AT(1))-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 pre ssure (BP) was continuously monitored (Finapres), and BP response to r epeated 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 ph armacokinetics 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 res ponse), 10.1 mm Hg (35.4 +/- 1.8%), and 17.5 mm Hg (58.7 +/- 1.8%), re spectively. SC-52458 produced dose-related increases in PRA and Ang II concentrations less than or equal to 10 h after drug intake. Plasma a ldosterone concentrations tended to be decreased for less than or equa l to 24 h after SC-52458 doses of greater than or equal to 100 mg. No drug-related side effects were observed. The pharmacokinetics were lin ear over the dose range of 10-150 mg (t(1/2) = 1.14-2.39 h). Efficacy was dose dependent, with a peak effect after 1 h. In conclusion, the n ovel AT(1)-receptor antagonist SC-52458 is well tolerated and orally a ctive. II produces a rapid-onset inhibition of the renin-angiotensin s ystem and reduces BP response to Ang II for greater than or equal to 1 0 h. These characteristics promise strong antihypertensive properties for SC-52458.