Cazaubon C, Gougat J, Bousquet F, Guiraudou P, Gayraud R, Lacour C, Roccon A, Galindo G, Barthelemy G, Gautret B
Sanofi Recherche, Montpellier, France.
J Pharmacol Exp Ther. 1993 May;265(2):826-34.
SR 47436, 2-n-butyl-3-[(2'-(1H-tetrazol-5-yl)-biphenyl-4-yl) methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one, is a new potent and selective AT1 angiotensin II (AII) receptor antagonist. It competitively inhibited [125I]AII binding to AT1 subtype receptors in rat liver membranes (IC50 = 1.7 nM) and did not interact with AT2 subtypes in rat adrenal cortical membranes. In rabbit aorta, SR 47436 inhibited contractions induced by 10 nM AII (IC50 = 4.0 nM) and shifted AII contractile response curves to the right in a parallel fashion, without total recovery of the maximal response. The potency of SR 47436 was higher than that of the lead compound, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5- yl)biphenyl-4-yl)methyl]imidazole (DuP 753) (rat liver binding: IC50 = 16 nM; rabbit aorta: IC50 = 26 nM), and equivalent to saralasin (IC50 = 1.8 and 2.7 nM, respectively). The high specificity of SR 47436 was demonstrated by its lack of activity (IC50 > 10 microM) on various other receptors, ionic channels and antiports and rabbit aorta contracted by norepinephrine and KCl, and its lack of inhibition of renin and converting enzyme. In conscious rats, SR 47436 as well as DuP 753 (0.1 to 3 mg/kg, i.v., and 0.3 to 30 mg/kg, p.o.) antagonized the AII-pressor response in a dose-related manner. In conscious dogs, SR 47436 (1-10 mg/kg, p.o.) was a more potent antagonist of the AII pressor response than DuP 753. In conscious chronically implanted cynomolgus monkeys, SR 47436 antagonized the AII-pressor response at 1 mg/kg (89% i.v. and 66% p.o.) much more strongly than DuP 753 at 10 mg/kg (83% i.v. and 20% p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)
SR 47436，即2-正丁基-3-[(2'-(1H-四氮唑-5-基)-联苯-4-基)甲基]-1,3-二氮杂螺[4,4]壬-1-烯-4-酮，是一种新型强效且选择性的AT1血管紧张素II（AII）受体拮抗剂。它能竞争性抑制[125I]AII与大鼠肝细胞膜上的AT1亚型受体结合（IC50 = 1.7 nM），且不与大鼠肾上腺皮质膜上的AT2亚型相互作用。在兔主动脉中，SR 47436抑制10 nM AII诱导的收缩（IC50 = 4.0 nM），并使AII收缩反应曲线平行右移，最大反应未完全恢复。SR 47436的效力高于先导化合物2-正丁基-4-氯-5-羟甲基-1-[(2'-(1H-四氮唑-5-基)联苯-4-基)甲基]咪唑（DuP 753）（大鼠肝结合：IC50 = 16 nM；兔主动脉：IC50 = 26 nM），与沙拉新相当（IC50分别为1.8和2.7 nM）。SR 47436对多种其他受体、离子通道和转运体缺乏活性（IC50 > 10 microM），对去甲肾上腺素和氯化钾收缩的兔主动脉也无活性，且不抑制肾素和转化酶，证明了其高特异性。在清醒大鼠中，SR 47436以及DuP 753（静脉注射0.1至3 mg/kg，口服0.3至30 mg/kg）以剂量相关方式拮抗AII升压反应。在清醒犬中，SR 47436（口服1至10 mg/kg）比DuP 753更有效地拮抗AII升压反应。在清醒慢性植入的食蟹猴中，SR 47436在1 mg/kg时（静脉注射89%，口服66%）比DuP 753在10 mg/kg时（静脉注射83%，口服20%）更强烈地拮抗AII升压反应。（摘要截短于250字）
