Shuichi Wakabayashi

Pharmacological properties of KT3-671, a novel nonpeptide angiotensin II receptor antagonist.

We examined pharmacological profiles of KT3–671, 2-propyl-8-oxo-l-[(2‘-(lH-tetrazole-5-yl) biphe-nyl-4-yl)methyl]-4,5,6,7-tetrahydro-cycloheptimidazole, a newly synthesized nonpeptide angiotensin II (AII) receptor antagonist in various in vitro and in vivo studies. KT3–671 displaced specific binding of [125I]Sar1 Ile8-AII to AT1 receptor with a Ki value of 0.71 ± 0.14 x 10-9M in rat liver membranes, but had no affinity for AT2 receptor in bovine cerebellar membranes (Ki > 10-5M). In isolated rabbit aorta, KT3–671 produced a parallel right-ward shift in the concentration-response curve for AH with a pA2 value of 10.04 ± 0.12, but had no effect on K.CI-, norepinephrine (NE)-, and serotonin (5-HT)-induced contractions. In conscious normotensive rats, KT3–671 (0.3–10 mg/kg, p.o.) inhibited the All-induced pressor response dose dependently. In renal arteryligated hypertensive rats, KT3–671 (0.1–3 mg/kg, p.o.) decreased arterial blood pressure (BP) dose dependently. The hypotensive action of 3 mg/kg KT3–671 was maintained for at least 24 h. These results suggest that KT3–671 is a potent AT1 subtype-selective and competitive nonpeptide AII receptor antagonist and has an orally active antihypertensive effect without agonistic activity.

Azulene derivatives as TXA2/PGH2 receptor antagonists--II. Synthesis and biological activity of 6-mono- and 6-dihydroxylated-isopropylazulenes.

In order to examine the correlation between activity and hydrophilicity of the side chain of sodium 3-[4-(4-chlorobenzenesulfonylamino)butyl]-6-isopropylazulene -1-sulfonate (KT2-962), a non-prostanoid TXA2/PGH2 receptor antagonist, one or two hydroxyl groups were introduced into the isopropyl moiety. A series of 6-hydroxylated-isopropylazulenes were synthesized by regioselective oxidation of 6-isopropylazulenes and their in vitro and in vivo antagonistic activities were studied. Both the primary and tertiary alcohols, monohydroxylated derivatives, exhibited potent biological activities comparable to unmodified 6-isopropylazulenes both in vitro and in vivo. In contrast, the activities of 1,2- and 1,3-diols of 6-substituted derivatives, markedly decreased, but recovered by O-isopropylidenation of the dihydroxyl moiety. These findings indicate that the moderate hydrophobicity of substituent at the 6-position of the azulene ring might be required for the activity and the size of the substituent at this position, not so rigid for keeping potent biological activity.

Pharmacologic properties of KT2-962 (6-isopropyl-3-[4-(p- chlorobenzenesulfonylamino)-butyl]-azulene-1-sulfonic acid sodium salt); a new TXA2/prostaglandin endoperoxide receptor antagonist.

Pharmacologic properties of KT2–962 (6-iso-propyl-3-[4-(p-chlorobenzenesulfonylamino)butyl]-azu-lene-1-sulfonic acid sodium salt, KT) were studied in isolated rat aorta, rat tail artery, rabbit aorta, rabbit renal artery, and pig coronary artery. KT competitively inhibited the contractions induced by thromboxane A2 (TXA2) mimetic, U46619 (pA2 values 9.95, 8.85, 7.87, 8.49, and 9.12, respectively). KT also inhibited the contraction of rabbit aorta induced by prostaglandin2α, (PGF2α, pA2 value 7.85) and the contraction of guinea pig ileum induced by LTD4 (pA2 value 5.48) but did not alter the contractions induced by norepinephrine (NE). Ca2+, serotonin, and histamine. KT did not alter the contractions of guinea pig ileum, which did not contract with U46619, induced by PGE2 and PGF2α, KT inhibited the aggregations of rabbit platelets induced by U46619, arachidonic acid, and collagen (IC50 values 7.9, 140, and 16 μM, respectively) but not those induced by ADP. It also inhibited the specific binding of TXA2/PGH2 receptor antagonist, [3H]SQ29,548, to rabbit gel-filtered platelets with an IC50 value of 1.5 × 10-8 M. In in vivo experiments with mice, oral administration of KT protected the U46619-induced sudden death with the minimum effective dose of 0.3 mg/kg and provided such protection for ≥8 h at 1.0 mg/kg. These results indicate that KT is a new nonpros-tanoid type TXA2/PGH2 receptor antagonist that is orally effective and long acting.

Characterization of the vasoinhibitory actions of KT2-230, a new benzothiazepine vasodilator derivative on isolated rabbit vascular smooth muscles: An alpha-adrenergic- and serotonergic-receptor antagonist

1. Pharmacological properties of KT2-230 (benzothiazepine derivative), a newly synthesized vasorelaxing agent, were studied. 2. In the anesthetized dogs, KT2-230 increased the femoral and vertebral blood flow without effect on systemic blood pressure. 3. In rabbit aorta, KT2-230, methysergide and phentolamine inhibited contractile responses to 5-hydroxytryptamine. 4. The response to norepinephrine was also inhibited by KT2-230 and phentolamine. Responses to histamine were not affected by KT2-230. 5. Responses to KCl and Ca2+ in K+ depolarized aorta in Ca2(+)-free medium were inhibited by a high concentration of KT2-230. 6. In rabbit iliac artery, KT2-230 inhibited the response to caffeine in Ca2(+)-free medium. 7. KT2-230 decreased total La3(+)-resistant Ca2(+)-binding at high affinity sites. 8. These results indicate that KT2-230 inhibits alpha 1-adrenoceptors and 5-HT-receptors and at high concentrations it inhibits slow Ca2(+)-channels. KT2-230 may inhibit the Ca2(+) release from caffeine- and agonist-sensitive Ca2+ stores.