PHARMACOLOGICAL PROFILES OF KRH-594, A NOVEL NONPEPTIDE ANGIOTENSIN-II-RECEPTOR ANTAGONIST

We studied pharmacologic profiles of KRH-594, dipotassium -ylidene]ami nocarbonyl]-1-cyclopentenecarboxylate, a novel angiotensin II (AII)-re ceptor antagonist. KRH-594 potently displaced specific binding of [I-1 25]-AII from AT(1) receptor with a K-i of 0.39 nM in rat liver membran es, but not from AT(2) receptor in bovine cerebellar membranes (K-i > 10 mu M). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 mu M], demonstratin g its high specificity toward AT(1) receptors. In isolated rabbit aort a, KRH-594 caused nonparallel shifts to the right of the dose-response curve to AII and decreased the maximal response with a pK(B) of 10.4. We evaluated the in vivo efficacy and the duration of action in freel y moving rats under nonfasting conditions. In normotensive rats, orall y administered KRH-594 inhibited AII-induced presser responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensiv e rats (SHRs), both KRH-594 (1 mg/kg p.o.) and losartan (10 mg/kg p.o. ) exerted similar blood pressure-reducing effects, and their effects w ere still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT(1) antagonist that may f ind its use in the treatment of human hypertension.