Masaru Kawakami

Pharmacological characterization of PABSA, an orally active and highly potent endothelin-receptor antagonist.

The pharmacological characterization of a nonpeptide endothelin (ET)-receptor antagonist, PABSA [(R)-(--)-2-(benzo[1,3]dioxol-5-yl)-N-(4-isopropyl-phenylsulfon yl)-2-(6-methyl-2-propylpyridin-3-yloxy)-acetamide hydrochloride] was studied. PABSA competitively inhibited the binding of [125I]-ET-1 to A7r5 cells expressing ET(A) receptors and of [125I]-ET-3 to COS cells expressing porcine ET(B) receptors with Ki values of 0.11 and 25 nM, respectively. PABSA inhibited ET(A) receptor-mediated and ET(B) receptor-mediated vasocontraction and ET(B) receptor-mediated vasorelaxation in isolated rabbit vessels with K(b) values of 0.46, 94, and 26 nM, respectively. The antagonist potency of PABSA for ET(A) receptor-mediated vasocontraction was 63- and 87-fold more potent than those of BQ-123 and bosentan, respectively, and was similar to those of TAK-044 and SB209670. Oral administration of PABSA (1-10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET- 1 (0.1 nmol/kg) in conscious normotensive rats. PABSA (10-100 mg/kg, p.o.) reduced blood pressure in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs), and stroke-prone spontaneously hypertensive rats (SHRSPs). The hypotensive effect of PABSA was sustained for > or =24 h in these rats. These results suggest that PABSA is a highly potent ET(A)-receptor antagonist with weak ET(B)-receptor antagonist activity. Because PABSA has a long duration of action in vivo, this antagonist should be useful in the therapy of ET-related disease.

Pharmacologic characterization of S-1255, a highly potent and orally active endothelin A receptor antagonist.

The pharmacologic properties of a novel nonpeptide endothelin (ET) receptor antagonist, S-1255 ([R]-[+]-2-[benzo(1,3)dioxol-5-yl]-6-isopropyl-4-[4-methoxyphenyl]-2H-chromene-3-carboxylic acid), was studied. [3H]S-1255 specifically bound to porcine aortic smooth muscle membranes expressing only ETA receptors with a Kd value of 0.39 n M. [3H]S-1255 binding was potently inhibited by ET-1 and selective ETA or ETA/ETB receptor antagonists, such as L-749329, SB209670, bosentan, and BQ-123, but the inhibitory effect of ET-3 and the selective ETB receptor antagonist, BQ-788, on the binding was weak. These inhibitory effects on [3H]S-1255 binding correlated well with those on [125I]ET-1 binding. S-1255 inhibited ETA receptor-and ETB receptor-mediated contractions in isolated rabbit femoral and pulmonary arteries with pA2 values of 8.8 and 6.3, respectively. The pA2 value of S-1255 for ETB receptor-mediated relaxation in isolated rabbit mesenteric artery was 7.4. Oral administration of S-1255 (0.3–10 mg/kg) caused dose-dependent inhibition of the pressor response to exogenous ET-1 (0.1 nmol/kg) in conscious normotensive rats, which was similar to that produced by intravenous administration (1 and 3 mg/kg). S-1255 (10 and 30 mg/kg, p.o.) significantly reduced blood pressure in deoxycorticosterone acetate–salt hypertensive rats from 6 h after administration, and the hypotensive effects were sustained up to 24–48 h. These results suggest that S-1255 is a highly potent and orally active ETA receptor antagonist.

Pharmacological Studies on a New Antihypertensive Agent, S-2150, a Benzothiazepine Derivative: 2. Hypotensive Effects in Normotensive and Hypertensive Rats

S-2150 is a new 1,5-benzothiazepine derivative possessing both calcium channel-blocking and alpha 1-adrenoceptor-blocking effects. In isolated rat thoracic aorta precontracted with KCl (18 mM), the 50% inhibitory concentration (IC50) value was 190 nM for S-2150, which was similar to that of diltiazem. In aorta precontracted with phenylephrine (0.3 microM), IC50 values of S-2150 and diltiazem were 29 nM and > 10 microM, respectively. The relative contribution of calcium channel-blocking and alpha 1-adrenoceptor-blocking activities to hypotension was determined by using anesthetized rats before and after masking of the alpha 1-receptors with prazosin. The hypotensive effect of S-2150 [0.3 and 1 mg/kg intravenously (i.v.)] was attenuated by 40% after prazosin treatment, whereas that of diltiazem was not. In conscious spontaneously hypertensive rats (SHRs), renal hypertensive rats, and normotensive rats, S-2150 [10, 30, and 60 mg/kg orally (p.o.)] caused dose-dependent hypotensive effects. The effect of S-2150 was 4-7 times more potent than that of diltiazem. There were no changes in the hypotensive effects with consecutive administration of S-2150 during 6-8 weeks in SHRs and stroke-prone SHRs (SHRSPs). In SHRSPs, S-2150 reduced the mortality by stroke and small arterial hyperplasia in abdominal organs and also ameliorated renal excretory function. These results suggest that S-2150 may be a useful antihypertensive agent possessing both calcium-antagonistic and alpha 1-adrenoceptor-blocking effects.