NEW NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS .3. SYNTHESIS, BIOLOGICAL PROPERTIES, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2-ALKYL-4-(BIPHENYLYLMETHOXY)PYRIDINE DERIVATIVES
NEW NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS .3. SYNTHESIS, BIOLOGICAL PROPERTIES, AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2-ALKYL-4-(BIPHENYLYLMETHOXY)PYRIDINE DERIVATIVES
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DOI：
10.1021/jm00061a016
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发表时间：
1993-04-30
影响因子：
7.3
通讯作者：
ROBINS, PJ
中科院分区：
文献类型：
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作者：
BRADBURY, RH;ALLOTT, CP;ROBINS, PJ
本文报道了一系列新的非肽类血管紧张素Ⅱ（AII）受体拮抗剂，它们是由在以前描述的拮抗剂中发现的联苯基四唑部分通过亚甲基氧基链与3-取代的2，6-二烷基吡啶的4-位连接而得到的。当使用豚鼠肾上腺膜制备物在体外结合试验中进行评价时，该系列化合物通常给出0.005-0.5 μ M范围内的IC 50值。发现各种取代基在吡啶环的3-位是有效的。在正常血压大鼠模型中静脉给药时，更有效的化合物抑制AII诱导的升压反应，ED 50值在0.1-1.0 mg/kg范围内。其中一种化合物2-乙基-5，6，7，8-四氢-4-{[2 '-（1H-四唑-5-基）联苯-4-基]甲氧基}喹啉（26）在两种大鼠模型中显示出良好的口服活性。在AII输注、清醒、血压正常大鼠中，在1-10 mg/kg po剂量范围内，该化合物表现出对升压反应的剂量相关抑制，在较高剂量下具有良好的作用持续时间。在肾性高血压大鼠模型中，化合物26以5 mg/kg po的剂量显示出快速和持续的血压降低。基于其特征，该化合物（命名为ICI D 6888）已被选择用于在志愿者中进行评价。
A novel series of nonpeptide angiotensin II (AII) receptor antagonists is reported, derived from linkage of the biphenylyltetrazole moiety found in previously described antagonists via a methyleneoxy chain to the 4-position of a 3-substituted 2,6-dialkylpyridine. When evaluated in an in vitro binding assay using a guinea pig adrenal membrane preparation, compounds in this series generally gave IC50 values in the range 0.005-0.5 muM. A variety of substituents was found to be effective at the 3-position of the pyridine ring. On intravenous administration in a normotensive rat model, the more potent compounds inhibited the AII-induced pressor response with ED50 values in the range 0.1-1.0 mg/kg. One of the compounds, 2-ethyl-5,6,7,8-tetrahydro-4-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methoxy}quinoline (26), demonstrated good oral activity in two rat models. At doses in the range 1-10 mg/kg po in AII-infused, conscious, normotensive rats, the compound exhibited a dose-related inhibition of the pressor response with a good duration of action at the higher doses. In a renal hypertensive rat model compound 26 showed a rapid and sustained lowering of blood pressure at a dose of 5 mg/kg po. Based on its profile, this compound, designated ICI D6888, has been selected for evaluation in volunteers.