Pharmacologic Profiles of KRH-594, a Novel Nonpeptide Angiotensin II-Receptor Antagonist

Abstract

We studied pharmacologic profiles of KRH-594, dipotassium (Z)-2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4 -thiadiazolin-2-ylidene]aminocarbonyl]-1-cyclopentenecarb oxylate, a novel angiotensin II (AII)-receptor antagonist. KRH-594 potently displaced specific binding of [125I]-AII from AT1 receptor with a Ki of 0.39 nM in rat liver membranes, but not from AT2 receptor in bovine cerebellar membranes (Ki > 10 microM). KRH-594 exhibited no affinity for 21 other receptors and two enzymes [50% inhibitory concentration (IC50) > 10 microM], demonstrating its high specificity toward AT1 receptors. In isolated rabbit aorta, 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 freely moving rats under nonfasting conditions. In normotensive rats, orally administered KRH-594 inhibited AII-induced pressor responses with a 50% inhibitory dose (ID50) of 0.39 mg/kg. In spontaneously hypertensive 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 were still significant at 24 h after drug administration. We concluded that KRH-594 is a specific and efficacious AT1 antagonist that may find its use in the treatment of human hypertension.

Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration

“…6B). A maximal MAP reduction at losartan dose of 10 mg/kg was about 30 mmHg (about 20% change of MAP), which is consistent with the results of other previous studies [21][22][23] and similar to those of fimasartan dose of 3 mg/kg. The vehicle-treated control groups also showed a slight decrease of MAP due to the normal circadian change of SHRs.…”

“…Although MAP levels between 8 and 23.5 h are not presented, it appears that circadian rhythms exhibited peak during nocturnal period, as has been previously reported for normotensive and hypertensive rats and humans. 23,24) SHRs are widely recognized model of essential hypertension with normal renin levels, which is at odds with accepted contribution of the RAS system to animal and human essential hypertension. Circulating kidney-derived renin is not elevated but arterial wall renin concentrations are increased in SHRs.…”

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

“…Such inhibition has been reported for azilsartan (Kohara et al, 1996), candesartan Wada et al, 1994Wada et al, , 1996Kohara et al, 1996;Nakano et al, 1997;Champion et al, 1998;Koike et al, 2001;Maillard et al, 2002a), eprosartan (Wang and Brooks, 1992), irbesartan Lacour et al, 1994;Christophe et al, 1995;Culman et al, 1999;Maillard et al, 2002a), losartan (Wong et al, 1990a,c; Abdelrahman (Wong et al, 1990b,d;Buhlmayer et al, 1991;Edwards et al, 1992a;Lin et al, 1992;Liu et al, 1992b;Bernhart et al, 1993;Cazaubon et al, 1993;Criscione et al, 1993;Leung et al, 1993;Noda et al, 1993;Shibouta et al, 1993;Dickinson et al, 1994;Schambye et al, 1994;Keiser et al, 1995;Mizuno et al, 1995;Hashimoto et al, 1997;Jin et al, 1997;Tamura et al, 1997a;Garcha et al, 1999;Inada et al, 1999;Maassen vandenBrink et al, 1999;Morsing et al, 1999;Balt et al, 2002;Guimarães et al, 2011;Wienen et al, 1992Wienen et al, , 1993Zhang et al, 1993…”

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“…Specifically, it contains a carboxylate group as Phe8, isoleucine side chain instead of benzene of Phe 8 and imidazole ring as His 6 . Compound H proved the most active and was over 12-fold more potent than the lead compound G. All the synthesized compounds were evaluated for their human AT 2 R affinity in a radio ligand binding assay measuring the displacement of CGP-42112A,a selective AT 2 R agonist 47 .…”