K. Tamura et al., PHARMACOLOGICAL PROFILES OF KRH-594, A NOVEL NONPEPTIDE ANGIOTENSIN-II-RECEPTOR ANTAGONIST, Journal of cardiovascular pharmacology, 30(5), 1997, pp. 607-615
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.