非肽血管紧张素II受体拮抗剂:一类新的抗高血压药物。

Blood vessels Pub Date : 1990-01-01 DOI:10.1159/000158821
P B Timmermans, D J Carini, A T Chiu, J V Duncia, W A Price, G J Wells, P C Wong, R R Wexler, A L Johnson
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引用次数: 16

摘要

阻断肾素-血管紧张素系统功能的最直接方法是在受体水平上拮抗血管紧张素II (AII)。然而,目前可用的AII受体拮抗剂,如saralasin,是仍然保留激动活性且缺乏口服生物利用度的肽。我们已经确定n -苄基咪唑,S-8307和S-8308是弱的,但选择性的非肽AII受体拮抗剂。这些初始先导物随后被转化为更有效的化合物,如EXP6155、EXP6803和EXP7711,同时保持了选择性。这些化合物取代3H-AII在肾上腺皮质膜和平滑肌细胞中的特定结合位点。在各种体内和体外制剂中,它们竞争性地抑制血管收缩剂对AII的反应,但不影响对KCl、去甲肾上腺素和抗利尿激素的反应。转化酶和肾素不受这些药物的影响。在肾性高血压大鼠和钠耗尽犬中,我们的化合物在静脉和口服(EXP7711)给药后可持续降低动脉压,并且不具有激动剂特性。综上所述,这些非肽结构是真正的竞争性AII受体拮抗剂,代表了一类新的有效抗高血压药物。
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Nonpeptide angiotensin II receptor antagonists: a novel class of antihypertensive agents.

The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.

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